Sage Journals: Discover world-class research

Abstract

Ovarian cancer comprises the most lethal gynecologic malignancy and is accompanied by the high potential for the incidence of metastasis, recurrence and chemotherapy resistance, often associated with a formation of ascitic fluid. The differentially expressed ascites-derived microRNAs may be linked to ovarian carcinogenesis. The article focuses on a number of miRNAs that share a common expression pattern as determined by independent studies using ascites samples and with regard to their functions and outcomes in experimental and clinical investigations.

Let-7b and miR-143 have featured as tumor suppressors in ovarian cancer, which is in line with data on other types of cancer. Although two miRNAs, i.e. miR-26a-5p and miR-145-5p, act principally as tumor suppressor miRNAs, they occasionally exhibit oncogenic roles. The performance of miR-95-3p, upregulated in ascites, is open to debate given the current lack of supportive data on ovarian cancer; however, data on other cancers indicates its probable oncogenic role. Different findings have been reported for miR-182-5p and miR-200c-3p; in addition to their presumed oncogenic roles, contrasting findings have indicated their ambivalent functions. Further research is required for the identification and evaluation of the potential of specific miRNAs in the diagnosis, prediction, treatment and outcomes of ovarian cancer patients.

Keywords

Ovarian cancer ascites effusion microRNA tumor tumor suppressor oncogene

1. Introduction

Of the various gynecologic malignancies, ovarian cancer is the deadliest, accounting for $\sim$ 314,000 new cases and $\sim$ 207,000 deaths worldwide annually [1]. The disease is usually diagnosed in the advanced stages, thus resulting in high levels of recurrence and poor patient outcomes, and survival rates that are substantially lower than those of patients diagnosed in the early stages of the disease [2, 3]. The advanced stages are often accompanied by the formation of ascites (also known as ascitic fluid, peritoneal/pleural fluid or effusion), i.e. the excessive accumulation of fluid within the peritoneal and/or pleural cavity. This fluid may also occur in the early stages of the disease. While survival rates are higher when ascitic fluid is not present in patients, they decrease dramatically in the advanced stages of the disease [4]. A large volume of ascites is an indicator of suboptimal cytoreduction, the increased risk of disease recurrence and a lower chance of progression-free and overall survival [5].

Ascites comprises a dynamic fluid environment that is rich in various components both at the cellular and extracellular levels, and it is suspected of playing a role in ovarian carcinogenesis. The cell components include tumor cells, lymphocytes, mesothelial cells and macrophages that occur in a solution comprising diverse types of molecules, including soluble angiogenic and growth factors, cytokines, chemokines and extracellular matrix components [6, 7, 8]. These components are suspected of contributing to cell growth, tumor invasion and resistance to TNF-related apoptosis-inducing ligands; however, the acellular fraction may contain anti-angiogenic and apoptosis-promoting factors [9, 10]. Ascites is capable of inducing WNT signaling in primary HGSC cells and the HGSC cell line. Moreover, patients whose ascites is unable to activate WNT pathways have shown considerably better outcomes, including overall survival [11]. An inflammatory tumor environment is associated with ascites; moreover, the increased cellular resistance of the tumor cells present and the development of venous thromboembolic events present significant risk factors for the patients concerned [12].

Finally, ascites contains a large fraction of nucleic acids including small, non-coding RNAs known as microRNAs (miRNAs), a large number of which participate in carcinogenesis in the form of key post-transcriptional gene expression regulators with important roles in several crucial biological processes [13]. They enter into the gene expression regulatory networks and are able to serve as oncogenes or tumor suppressors depending on the phenotype they induce, the targets they modulate, and the tissue in which they function [14]; alternatively, they may be associated with resistance to the chemotherapy/radiotherapy treatment of ovarian cancer [15].

Ascites-derived miRNAs are thought to be closely related to ovarian carcinogenesis since ascites and the soluble factors thereof provide extracellular cues that drive cancer progression via increased cell renewal, proliferation, migration and invasion [11], which eventually results in the spread of cancer cells within the peritoneal cavity and the formation of metastases.

Various biological sources contribute to both the cellular and extracellular fractions of miRNAs in ascites. They originate from the blood as plasma filtrate and other cells including tumor cells and various types of leukocytes. All these components are capable of featuring differentially expressed miRNAs during the course of carcinogenesis. Several recent studies have focused on the differential expression of miRNAs using cellular and extracellular ascites samples, and have identified potential candidate miRNAs [16, 17, 18, 19, 20, 21, 22]. However, the specific biological functions of ascites-derived miRNAs in promoting ovarian cancer remain largely unknown.

This study provides a review of recent progress in miRNA research based on ascites samples and assesses the level of consistency of the various studies aimed at elucidating the potential roles of dysregulated miRNAs in ovarian cancer. The study focuses in detail on a number of particularly consistently differentially expressed miRNAs found in ascites samples and their potential functions in ovarian carcinogenesis: the potential tumor suppressor miRNAs let-7b, miR-26a, miR-145 and miR-143, and the potential oncogenic miRNAs miR-95-3p, miR-182-5p and miR-200c-3p. The basic characteristics of the various studies considered are listed in Table 1.

2. Ascites as the source of biomarkers for ovarian cancer

2.1 Cellular fractions of ascites

A study by Vaksman et al. [16] that focused on cell-derived miRNAs explored the differences in the expression of miRNAs between ovarian cancer cells in tumors and ovarian cancer-associated effusions. While six of the miRNAs were highly expressed only in primary carcinomas and 12 miRNAs were upregulated only in effusions, 16 miRNAs were highly expressed in both groups. The comparison of the cellular content of the effusions and primary carcinomas revealed the elevated expression of let-7f, miR-182, miR-210, miR-200c, miR-222 and miR-23a, and reduced levels of miR-145 and miR-214 [16]. The recent study of the cell pellets of effusions revealed the expression of 9 miRNAs (miR-29a, miR-31, miR-99b, miR-182, miR-210, miR-221, miR-224 and miR-342) with respect to potential clinical outcomes. The longer overall survival of metastatic high-grade serous carcinoma patients has been associated with the higher expression of miR-29a [20].

Table 1
Differential expression of microRNAs in various types of ascites-derived samples associated with ovarian cancer

Histological type	Upregulated expression of microRNAs	Downregulated expression of microRNAs	Sample	Control/Comparison to	Number of samples/method	Reference
Mostly serous ovarian carcinoma	let-7f, miR-182-5p, miR-210-3p, miR-200c-3p, miR-222-3p, miR-23a-3p	miR-145-5p, miR-214-3p	Cells of the effusion	Primary carcinoma sample	miRNA array screening: 13 effusions, 8 primary carcinomas (miRvana miRNA Bioarray, version 2, Ambion). Validation: 30 effusions, 15 primary carcinomas (qPCR)	16
Serous ovarian carcinoma		miR-132, miR-26a, let-7b, miR-145, and miR-143	Ascites/Serum	Control serum	Screening: Affymetrix miRNA V2.0 Array. Ascites ( $n=$ 2), serum ( $n=$ 1). Validation: serum of 18 patients and 12 normal controls (qPCR)	17
Serous ovarian carcinoma	miR-21		Cells and exosomes of the effusion	Nonneoplastic peritoneal effusions	Cancer: 10 peritoneal effusions. Controls: 10 peritoneal effusions (qPCR)	18
Mostly serous ovarian carcinoma	miR-127-3p, miR-129-3p, miR-133a-3p, miR-133b, miR-134-5p, miR-140-5p, miR-145-5p, miR-152-3p, miR-219-5p, miR-323-3p, miR-328-3p, miR-346, miR-365a-3p, miR-376c-3p, miR-422a, miR-452-5p, miR-532-3p, miR-598-3p, miR-95-3p. These miRNAs were suggested as specific for this type of sample.	n/a	Effusion supernatant-derived exosomes	Effusion-derived tumor cells	OC effusion exosomes ( $n=$ 9, pooled), RMC effusions ( $n=$ 8, pooled, used as benign control), OC effusion-derived cells ( $n=$ 13, pooled). TaqMan miRNA array (qPCR)	19
Serous ovarian carcinoma	miR-29a		Cells of the effusion	Only survival analyses	148 effusions (qPCR)	20
High-grade serous ovarian carcinoma (screening)	Screening using TaqMan cards A (consistently differentially expressed miRNAs using both Ct $\leqslant$ 40) and Ct $<$ 35 cut-offs: miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-204-5p, miR-141-3p, miR-203a-3p, miR-193b-3p, miR-10b-5p, miR-886-3p, miR-31-5p, miR-10a-5p, miR-452-5p, miR-99a-5p, miR-224, miR-886-5p,	Screening using TaqMan cards A (consistently differentially expressed miRNAs using both Ct $\leqslant$ 40) and Ct $<$ 35 cut-offs: miR-451a, miR-185-5p, miR-15b-5p, miR-223-3p, miR-142-3p, miR-16-5p, miR-652-3p, miR-126-3p, miR-26b-5p, miR-19a-3p, miR-20a-5p, miR-19b-3p, miR-301a-3p, miR-20b-5p,	Supernatant fraction of ascites	Healthy control plasma (post-menopausal)	TaqMan MicroRNA array screening (5 ascitic fluid samples, 6 control plasma samples) (qPCR)	21

Table 1, continued
Histological type	Upregulated expression of microRNAs	Downregulated expression of microRNAs	Sample	Control/Comparison to	Number of samples/method	Reference
	miR-95-3p, miR-100-5p, miR-99b-5p, miR-483-5p, miR-574-3p, miR-342-3p, miR-146b-5p, miR-155 Screening using TaqMan cards B (cut-off Ct $<$ 35): miR-1290, miR-10b-3p, miR-1274A, miR-99b-3p, miR-1260, miR-1300, miR-720, miR-34a-3p, miR-30a-3p, miR-1291	miR-140-5p, miR-140-3p, miR-106b-5p, miR-25-3p, miR-374a-5p, miR-93-5p, miR-192-5p, miR-29c-3p, miR-199a-3p, let-7b, miR-302b-3p, miR-17-5p, miR-532-3p, miR-590-5p, miR-208a-3p, miR-486-5p, miR-425-5p, miR-145-5p, miR-195-5p, miR-324-3p, miR-454-3p, miR-30c-5p, miR-191-5p, miR-618, let-7a, let-7d, miR-30b-5p, miR-26a-5p, miR-221-3p, miR-194-5p, miR-181a-5p, miR-92a-3p, miR-186-5p, miR-532-5p, miR-501-5p, let-7g, miR-28-5p Screening using TaqMan cards B (cut-off Ct $<$ 35): miR-766, miR-223-5p, miR-30d, miR-30a-5p, miR-151-5p, miR-7-1-3p, miR-550, miR-93-3p, miR-1180
High-grade serous ovarian carcinoma (HGSOC) and primary ovarian carcinomas (serous, endometrioid, mucinous), ascites and lavages (both malignant and non-malignant) (validations)	miR-200a, miR-200b, miR-200c, miR-141, miR-429, miR-1290, miR-30a-5p		Supernatant fraction of ascites and/or peritoneal lavages	Healthy control plasma (post-menopausal)	TaqMan individual microRNA assays (validation), 9 HGSOC cancer ascitic fluid samples versus 34 controls (qPCR). Another set: Ascitic fluid, serous ( $n=$ 10), endometrioid ( $n=$ 2), mucinous ( $n=$ 3). Lavages, serous ( $n=$ 8). Control plasma ( $n=$ 34) (qPCR)	21
Mostly high-grade serous ovarian carcinoma	miR-203a-3p, 204-5p, 135b-5p, miR-182-5p	miR-451a	Supernatant fraction of ascites	Healthy control plasma (post-menopausal)	TaqMan individual microRNA assays (validation), 12 cancer samples, 12 controls (qPCR)	22
Serous ovarian carcinoma		let-7b, miR-23b-3p, miR-29a-3p, miR-30d-5p, miR-205-5p, miR-720	Extracellular vesicles in ascites	Peritoneal fluid from subjects with benign cysts or endometrioma	8 ovarian cancer versus 10 benign samples, 18 miRNAs tested (qPCR)	24

Notes: HGSOC, high-grade serous ovarian carcinoma, OC, ovarian carcinoma; RMC, reactive mesothelial cells; n/a, not known/available; qPCR, Real-time (quantitative) polymerase chain reaction.

2.2 Exosome/extracellular vesicle fractions of ascites

Exosomes comprise small extracellular vesicles (EV) up to 100 nm in diameter that occur in a vast range of body fluids and which are suspected of playing a role in intercellular communication while harboring a miRNA fraction along with other components. Cell-free RNAs packaged within EVs (microvesicles, exosomes or apoptotic bodies) are considered to be the most stable and, thus, the most effective factor in terms of driving the intercellular crosstalk process. Moreover, they are considered to be potential innovative biomarkers [23].

Vaksman et al. [19] compared the miRNA expression of pooled samples of effusion supernatants ( $n=$ 9) with pooled reactive mesothelial cells (RMC, $n=$ 8) and pooled effusion-derived tumor cells ( $n=$ 13). 99 miRNAs were identified via miRNA profiling as evincing higher expression levels (Ct $<$ 30) in exosomes than in effusion supernatants. 102 miRNAs exhibited a higher expression in OC cells and 14 miRNAs were highly expressed in RMC. Interestingly, the authors attempted to assess the origin of the studied miRNAs and suggested (indirectly based on the expression pattern) that 75% of the miRNAs in the effusion supernatant may have originated in OC cells. Moreover, 19 effusion supernatant-specific miRNAs were identified with unknown origins. The authors also determined the association of the miRNA expression with the outcomes of the patients. High levels of miR-21, miR-23b and miR-29a were associated with poor progression-free survival rates, and the high expression of miR-21 correlated with poor overall survival rates [19].

Cappellesso et al. [18] focused on the expression of a known oncogenic miRNA, i.e. miR-21 and found it to be elevated in OC cells and exosomes extracted from peritoneal effusions associated with ovarian serous carcinomas compared to nonneoplastic controls.

Finally, Yamamoto et al. [24] assessed the expression of 18 miRNAs derived from extracellular vesicles in ovarian cancer-derived ascites and compared them with peritoneal fluid from subjects with benign cysts or endometrioma. Six of the tested miRNAs were found to be underexpressed in the pathological samples.

2.3 Whole extracellular fractions of ascites

A study on miRNA expression in the extracellular fraction of ascites by Chung et al. [17] examined ascites, serum and tumor tissues from two ovarian cancer patients and one healthy control. In total, 2222 types of miRNAs were identified, while five miRNAs (miR-132, miR-26a, let-7b, miR-145 and miR-143) were found to be consistently underexpressed in the cancer samples. Further validation using only the serum samples of 18 patients and 12 normal volunteers confirmed the significant underexpression of four miRNAs (miR-132, miR-26a, let-7b, miR-145). Unfortunately, the authors did not provide detailed data from the screening phase in which they identified 95 down-regulated miRNAs and 88 up-regulated miRNAs.

Our own research focused on the extracellular fraction of ascitic fluid and expression of miRNAs involving the comprehensive screening of 754 unique human miRNAs and validation of selected candidate miRNAs and the comparison thereof with the profiling of tumor miRNAs that are involved in ovarian cancer [21, 22]. The large-scale screening phase indicated that 153 miRNAs were differentially expressed [21], among which members of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) were the most remarkably overexpressed, as was miR-1290. The validation phase served to prove the high-expression pattern of miR-200 family miRNAs and the relatively low overexpression of miR-30a-5p; however, a follow-up study failed to prove the overexpression of miR-1290 [22]. Moreover, miR-200b tentatively appeared to comprise a suitable prognostic marker that evinced a shorter overall survival time in the high-expression group (hazard ratio [HR]: 4.04, mean survival 24 months) than in the low expression group (HR: 0.25, mean survival 44 months) [21]. Several candidate miRNAs (miR-203a-3p, miR-204-5p, miR-451a, miR-185-5p, miR-135b-5p, miR-182-5p) were also evaluated in a follow-up study [22]. Three of the miRNAs (miR-203a-3p, 204-5p, 135b-5p) were found to be highly overexpressed, miR-182-5p was slightly (6-fold) but significantly overexpressed, and miR-451a was significantly underexpressed in ascitic fluid relative to the control plasma [22].

3. Expression pattern of ascites-derived miRNAs in ovarian cancer

As mentioned above, the expression of ascites-derived miRNAs has been investigated with respect to a variety of types of samples including cells, whole extracellular fractions and parts of extracellular fractions such as exosomes and extracellular vesicles. Although all these parts may be associated with ovarian carcinogenesis, their individual impact on carcinogenesis and usefulness as potential biomarkers remains to be determined.

The following text provides an assessment of the consistency of the results in terms of providing a more comprehensive picture of miRNA deregulation in ovarian cancer. The comparison of the results of available miRNA expression studies revealed their very limited deregulation overlap. However, several miRNAs appeared to be consistently altered, thus suggesting their roles in ovarian cancer.

Of the deregulated miRNAs, let-7b was observed to be consistently down-regulated in serum [17], ascites [21] and extracellular vesicles [24]. Downregulated miR-26a and miR-145 have been observed in [17, 21], as well as for miR-145 in [16], while miR-143 was down-regulated in [17, 21] within a specific data group (Ct $<$ 40). Up-regulated miRNAs comprised miR-95-3p [19, 21], miR-182-5p [16, 22] and miR-200c-3p [16, 21]. We subsequently reviewed the data available on these miRNAs with concern to ovarian and other cancers so as to assess their presumed functions in ovarian carcinogenesis.

3.1 Potential tumor suppressor miRNAs let-7b, miR-26a, miR-145 and miR-143, and potential oncogenic miRNAs miR-95-3p, miR-182-5p and miR-200c-3p in focus

Presuming that a common expression pattern reflects their shared assumed functions, we explored the above-mentioned miRNAs aimed at revealing their potential roles in ovarian carcinogenesis in conjunction with previously conducted investigations.

3.1.1 Let-7b

The down-regulation of miRNA let-7b has been observed in three independent studies that focused on ascites [17, 21, 24], which tends to suggest its tumor suppressing role in ovarian cancer. Other literature data on the expression of let-7b in ovarian cancer is both scarce and controversial. Supporting the tumor suppressing view, previous investigations determined the down-regulation of let-7b in tumor tissues [25, 26]. Recently, we identified let-7b as the sixth most down-regulated miRNA (-25-fold) within a specific data set (Ct $\leqslant$ 40) from the high-throughput screening of cancer tissue samples compared with the controls, thus indicating potential tumor suppressing functions in ovarian carcinomas [22]. Conversely, the earlier metanalysis of studies that addressed the clinicopathological functions and prognostic values of individual let-7 family members identified elevated levels of let-7b as a poor prognostic factor in high-grade serous ovarian cancer [27].

Nevertheless, strong recent experimental and clinical evidence has demonstrated the opposite pattern of the functioning of let-7b in ovarian cancer [28]. This study revealed the negative association of let-7b with the histological type and grade, FIGO stage and lymph node metastatic status. In vitro, let-7b mimics acted to slow down A2780 and SKOV3 cell proliferation and migration, while let-7b inhibitors served to increase the numbers of migrated cells. Finally, the results suggested that high levels of KDM2B in ovarian cancer may inhibit the expression of let-7b, while let-7b inhibition acted to accelerate xenografted tumor growth in mice [28].

Regarding other cancers, let-7b has been repeatedly determined down-regulated in cancer tissues and cell lines compared to the controls. With concern to hepatocellular carcinoma, the decreased expression of let-7b was associated with a poor prognosis, whereas this miRNA was observed to inhibit cell proliferation through the upregulation of p21 in a recent study [29]. Similarly, Wang et al. [30] observed the remarkable down-regulation of let-7b in hepatocellular cancer (HCC) tissues. Experimentally overexpressed let-7b acted to decrease the expression of $\beta$ -catenin and c-Myc, and inhibited HCC cell proliferation [30]. Han et al. [31] demonstrated the tumor suppressive effects of let-7b in gastric cancer. Using a cisplatin-resistant gastric cancer cell line (SGC7901/DDP), the authors discovered that the low expression of let-7b was associated with cisplatin resistance, and they experimentally confirmed this finding using let-7b mimics that increased the cytotoxicity of DDP to SGC7901/DDP cells. Conversely, the knockdown of let-7b resulted in reduced sensitivity. Primary tumor growth was also observed to be reduced by let-7b mimic transfection [31]. A further study [32] revealed that let-7b was down-regulated in castration-resistant prostate cancer tissues and the C4-2 cell line. The overexpression of let-7b repressed cell proliferation and invasion in vitro and tumor growth in vivo [32]. Moreover, the overexpression of let-7b inhibited the proliferation of A375 and A2058 cells in melanoma via the targeting of UHRF1 [33]. Taken together, the vast majority of results indicate the tumor suppressing effects of let-7b in cancer.

3.1.2 miR-26a ( $=$ miR-26a-5p)

Three other miRNAs (miR-26a, miR-145, miR-143) have been consistently reported to be downregulated in ascitic fluid-based samples (see above). Several novel reports support the role of miR-26a ( $=$ miR-26a-5p) as an ovarian cancer inhibitor. We determined miR-26a down-regulated (-6-fold) within a specific data set (Ct $\leqslant$ 40) from the screening of ovarian cancer tissue samples compared to the controls [22]. Gao et al. [34] analyzed the expression of miR-26a in ovarian cancer patient tissues and the SK-OV-3 and A2780 cell lines, where low miR-26a and high TCF12 expressions were observed. TCF12 was identified as the direct target of miR-26a, while the experimental upregulation of miR-26a inhibited the proliferation, migration and invasion of, and induced apoptosis in, ovarian cancer cells [34]. Sun et al. [35] demonstrated the reduced expression of miR-26a in ovarian cancer tissues and a negative association with the expression of Cdc6. Further, the expression of miR-26a was associated with the differentiation and stage of cancer cells. Using miRNA-26a mimics, the proliferation and colony formation rate was reduced in SKOV3 cells and ES2 cells, while apoptosis was induced following transfection. Interestingly, contrasting findings were reported by Shen et al. [36] who revealed the overexpression of miR-26a in ovarian cancer and increased miR-26a plasma levels that distinguished the patients from the healthy controls. Experimentally, the ectopic expression of miR-26a in SKOV3 and ES2 cells enhanced both cell proliferation and clonal formation. An in vivo experiment using mice and the observation of the formation of xenograft tumors following the injection of SKOV3 cells transfected with either miR-26a or anti-miR-26a also indicated that the inhibition of miR-26a acted to suppress tumor formation [36].

The decreased expression and inhibitory roles of miR-26a that have been reported with respect to the progression of tumor/cell lines in tongue squamous cell carcinoma [37], non-small cell lung cancer [38] and hepatocellular carcinoma serve to support its tumor suppressing functions [39]. With respect to hepatocellular carcinoma, it should be noted, however, that opposite findings have also been reported [40]. This study revealed that on the one hand miR-26a promoted invasion/metastasis by inhibiting PTEN and, on the other, inhibited cell proliferation by repressing EZH2, thus suggesting the complexity of the regulation roles of miR-26a in cancer [40]. However, again with concern to hepatocellular cancer, miR-26a has recently been reported to be downregulated in carcinoma tissues and cells lines; miR-26a mimics served to inhibit cell proliferation and enhanced the doxorubicin sensitivity of hepatocellular carcinoma cells by targeting aurora kinase A [41]. Similarly, the activity of miR-26a as a tumor suppressor that targets FBXO11 acted to inhibit the proliferation, migration and invasion of hepatocellular carcinoma cells [42].

The ambiguity of the findings on miR-26a has also been demonstrated with respect to prostate and breast cancers. Concerning prostate cancer cells, miR-26a was observed to be overexpressed, the expression of PTEN (the target of miR-26a) was lower, and the experimental inhibition of miR-26a resulted in enhanced cell apoptosis, weakened proliferation ability, and an arrested cell cycle at the G0/G1 phase, thus suggesting the oncogenic roles of miR-26a in prostate cancer [43]. Huang et al. [44] determined the opposite findings for breast cancer, concerning which miR-26a-5p was downregulated in cancer tissues and cells lines and was associated with a poor prognosis. Moreover, this miRNA acted to inhibit breast cancer cell growth by suppressing the expression of RNF6. miR-26a serum levels were found to be reduced for gastric cancer [45]. Other reports have been published that identified the relatively tumor suppressing functions of miR-26a in a variety of other cancers such as colorectal cancer [46], lung cancer [47], bladder cancer [48], pancreatic ductal adenocarcinoma [49], cervical cancer [50], melanoma [51] and nasopharyngeal cancer [52].

3.1.3 miR-145 ( $=$ miR-145-5p)

Reports on a further consistently expressed miRNA in ascites, i.e. miR-145 ( $=$ miR-145-5p), indicate its down-regulation in ovarian cancer and, thus, its tumor suppressive role. In two of the first studies to be conducted on miRNAs in ovarian cancer, Iorio et al. [53] and Nam et al. [25] determined miR-145 to be one of the most down-regulated miRNAs in ovarian tumors versus normal ovary tissue; moreover, a large number of recent reports that consider the cell lines, tumors or serum of affected patients have indicated a similar pattern. In addition, several mRNA targets associated with sensitivity or resistance to chemotherapy and clinical outcomes have been identified. Wu et al. [54] reported miR-145 to be downregulated in ovarian cancer tissues, cell lines and in serum samples associated with ovarian cancer. Further, the same study demonstrated that this miRNA suppresses p70S6K1 and MUC1 [54]. In subsequent investigations, the down-regulation of miR-145 in cancer-associated samples was observed to be linked with enhanced proliferation, migration and invasion, the in vivo tumorigenicity of EOC cells and the overexpression of other direct miR-145 targets, including Cdk6 and Sp1 [55], c-Myc [56], metadherin (MTDH, [57]), HMGA2 [58], TRIM2 [59], MUC1 [60], D-type cyclin 2, cyclin D2 (CCND2), E2F transcription factor 3 (E2F3) [61], SMAD4 [62] and YTHDF2 [63]. Several reports have indicated that a higher miR-145 expression may be linked to improved survival rates as observed for both tissues [64, 65] and for serum [66]. The elevated expression of miR-145 has also been associated with increased sensitivity to paclitaxel [55]. We observed that miR-145 was consistently down-regulated (-9-fold) in ovarian cancer tumors compared with the controls [22]. Only two investigations have reported opposite or controversial findings for miR-145 in ovarian cancer. Wang et al. [67] observed upregulated levels of miR-145 in plasma and its down-regulated expression in tumors. Focusing on exosomes, Kim et al. [68] reported the higher expression of miR-145 in serum exosomes in a cancer group than in a non-cancer group (benign and borderline tumors). The investigation of other cancers imply the tumor suppressing roles of miR-145 with respect to non-small cell lung cancer (NSCLC, [69]), breast cancer [70] and pancreatic cancer [71].

3.1.4 miR-143 ( $=$ miR-143-3p)

The potential tumor suppressor miR-143 ( $=$ miR-143-3p) has been investigated in a number of studies, one of the most recent of which [72] focused on the roles of miR-143 in chemoresistance using chemoresistant (A2780/CDDP) and non-resistant (A2780) ovarian cancer cell lines. In line with its presumed tumor suppressor roles, decreased cisplatin resistance in A2780/CDDP has been associated with the overexpression of miR-143 while the inhibition of miR-143 resulted in decreased A2780 sensitivity to cisplatin.

According to recent investigations, miR-143 may interact with competing endogenous (ce)RNA such as lncRNA CDKN2B-AS1 [73], thus acting to reduce its expression. The decreased expression of miR-143 may, in turn, eventually lead to the derepression of the miR-143-3p target SMAD3 and, finally, to the progression of ovarian cancer. A similar interaction was noted for lncRNA MCM3AP-AS1 that acts as an oncogenic lncRNA by binding to miR-143-3p and, thereby, promoting the expression of transforming growth factor-beta-activated kinase 1 (TAK1) [74]. Another lncRNA, i.e. lncRNA urothelial carcinoma-associated 1 (UCA1) was observed to be upregulated in cisplatin-resistant patient tissues and cell lines, and its repression promoted the expression of miR-143 [75]. Lin et al. [76] observed that the inhibition of MALAT1 resulted in an increase in the expression of miR-143-3p. Guan et al. [77] explored the mechanisms underlying the transforming growth factor-beta (TGF-beta) 1-mediated regulation of the cystatin B (CSTB) progression marker and links to the expression of miR-143. By exploring the TGF-beta/miR-143-3p/CSTB axis of the regulatory interactions, the authors proved that the downregulated expression of miR-143 was associated with the overexpression of its target CSTB. Moreover, higher levels of CSTB expression were associated with the poor overall survival rate of patients with ovarian cancer. TGF-beta 1 treatment induced the upregulation of miR-143, while the knockdown of CSTB acted to decrease ovarian cancer cell proliferation [77]. Via the identification of transforming growth factor (TGF)-ss-activated kinase 1 (TAK1) as a further potential miR-143 target, Shi et al. [78] observed a similar miR-143 deregulation pattern. The decreased expression of miR-143 was noted in ovarian cancer tissues and in three cell lines, i.e. SKOV3, ES2 and OVCAR3, while its upregulation acted to reduce cell proliferation, migration and invasion in vitro, and inhibited the growth of ovarian tumors in vivo in a xenograft experiment [78].

A further study that determined similar results [79] observed lower levels of the expression of miR-143 and identified RalA-binding protein 1 (RALBP1) as another potential target of this miRNA. Moreover, transfection with miR-143-3p mimics and RALBP1 siRNA was observed to promote the apoptosis of ovarian cancer cells [79]. Similar findings were also reported by Wang et al. [80] in a study in which downregulated miR-143 was associated with stage, grade and lymph node metastasis in patients. The investigation of the behavior of ovarian cancer cell lines in vitro revealed the elevated expression of miR-143-inhibited cell proliferation, migration and invasion, while connective tissue growth factor (CTGF) was shown to comprise a direct miR-143 target [80]. Our screening study revealed the consistent down-regulation (-10-fold) of miR-143 in ovarian cancer tissues compared to the controls [22]. Similar findings concerning other cancers also suggest the tumor-suppressing role of miR-143 in e.g. colorectal cancer [81] and lung cancer [82].

3.1.5 miR-95 ( $=$ miR-95-3p)

Two studies on ovarian cancer that employed ascites samples, concluded that miR-95 ( $=$ miR-95-3p) may function as an oncogenic miRNA [19, 21]. However, no other reports on miR-95-3p expression alterations and its potential functional biological roles have been published with respect to ovarian cancer. Interestingly, we did not determine any significant alterations during the screening of ovarian cancer tumors and the controls [22]. Reports on other cancers generally provide supporting results. Huang et al. [83] proposed miR-95 as an oncogenic miRNA in colorectal cancer, the evidence for which comprised high levels of expression in tumor tissues and its in vitro/in vivo behavior. Other reports also proved the oncogenic roles of miR-95-3p in colorectal cancer [84, 85, 86, 87], gastric cancer [88] and prostate cancer [89]. However, controversial results have recently been reported with respect to colorectal carcinomas (CRC) suggesting miR-95-3p as potential tumor suppressor that is downregulated in CRC tissues with low levels that are associated with a poor prognosis. In vitro, overexpressed miR-95-3p was found to inhibit cell proliferation, colony formation and metastasis; moreover, this behavior was also observed in vivo [90]. These results are in direct contradiction to previous investigations on this type of cancer. Overall, it is presumed that miR-95-3p exerts oncogenic functions as noted in ovarian cancer based on the research of ascites; however, it is important to exercise caution in view of the current lack of proof with concern to ovarian tumor tissues.

3.1.6 miR-182-5p

The overexpression of miR-182-5p in ascitic fluid indicates its oncogenic roles in ovarian cancer. This view has generally been supported via a number of studies that determined that miR-182-5p comprises one of the most upregulated miRNAs. Elgaaen et al. [91] identified miR-200 family members and miR-182-5p as the most overexpressed miRNAs in high-grade serous ovarian carcinomas and clear cell ovarian carcinomas as compared to ovarian surface epithelium. Similarly, miR-182-5p was found to be among the eight most overexpressed miRNAs and was used for discriminating ovarian cancer tissues from normal tissues with 97% sensitivity and 92% specificity [92]. Moreover, Marzec-Kotarska [93] identified miR-182-5p as the sixth most overexpressed miRNA compared to normal ovarian tissue and its expression correlated with significantly shorter overall survival rates. In line with these studies, Wang et al. [94] suggested that miR-182-5p is upregulated in ovarian cancer tissues and cell lines and that it promotes cell proliferation and invasion. The long non-coding RNA ADAMTS9-AS2 that evinces a decreased expression in cancer samples has been identified as a miRNA sponge, and FOXF2 as a direct target for miR-182-5p in ovarian cancer [94]. The most recent support for the oncogenic view of miR-182-5p is provided by Wang et al. [95] who determined that circMTO1 inhibits the proliferation and invasion of ovarian cancer cells and sponged miR-182-5p, while supporting the expression of KLF15. Nevertheless, according to a recent investigation [96], miR-182-5p is downregulated in ovarian cancer tissues and cells and its overexpression acts to sensitize ovarian cancer cells to cisplatin. Similarly, the roles of miR-182-5p in other cancers appear to be ambivalent. For example, it was observed to be downregulated in colon cancer tissues and cells, whereas in vitro, the overexpression of miR-182-5p acted to repress the proliferation of colon cancer cells, colony formation, migration and invasion, and triggered G1 arrest and apoptosis [97]. Conversely, it was observed to be upregulated in non-small cell lung cancer [98]. These contradictions thus suggest the need for the further research of miR-182-5p and its various roles in carcinogenesis.

3.1.7 miR-200c-3p

miR-200c-3p is a member of the miR-200 family of miRNAs, the various members of which (miR-200a, -200b, -200c, -141 and -429) were initially considered to comprise oncogenic miRNAs in ovarian cancer due to their overexpression in a variety of types of samples. Our studies revealed the remarkably elevated expression of miR-200 family members in ovarian cancer tissues as well as in ascites [21, 22]. Similar evidence from initial reports [53, 25] has indicated that miR-200 family members evince important roles in terms of promoting ovarian carcinogenesis while being upregulated in cancer samples. However, other data (obtained mainly from experimental studies) has suggested the opposite expression pattern; thus, the roles of miR-200c and/or other family members will require further attention (e.g. [99, 100]).

Though findings based on other cancers may serve to support the conclusion that miR-200 family members function mainly as tumor suppressors and metastatic inhibitors evincing suppressive effects on cell transformation, cancer cell proliferation, migration, invasion, tumor growth and metastasis [101], the reported effects of the miR-200 family with concern to ovarian cancer are less consistent. The somewhat controversial results have triggered a plethora of research that both provides additional insight into miR-200 family regulations in cancer and suggests further inconsistencies and doubts. The results of diagnostic metanalysis have revealed that miR-200c-3p (along with miR-200a) comprises a reliable diagnostic marker with an upregulated expression for ovarian cancer that evinces a pooled sensitivity of 0.75 and specificity of 0.66. Moreover, it is suspected that both of these miRNAs contribute to EOC progression via their effect on cellular adhesion processes [102]. Nevertheless, the complex roles of the miR-200 family in ovarian carcinogenesis could be linked to differing expression in various stages of disease progression and different ovarian cancer subtypes. Moreover, the reproducibility of the various results obtained on cell lines requires further investigation. Meanwhile, the supporting and conflicting findings published to date serve to reinforce the confusing view of the roles of the miR-200 family in ovarian cancer.

The results of experimental research suggest that the miR-200 family suppresses epithelial to mesenchymal transition and enhances mesenchymal to epithelial transition processes. For example, Bendoraite et al. [103] focused on the expression of the miR-200 family and ZEB1/2 in ovarian cancer. Along with the up-regulation of the miR-200 family, the authors observed the diminished expression of ZEB1/2, suggested reciprocal regulation between the miR-200 family miRNAs and ZEB transcription factors and proposed a model for mesothelial-to-epithelial transition (MET) in the course of the progression of ovarian cancer. Jabbari et al. [104] determined that the transient overexpression of miR-200 family members in metastatic ovarian cell lines induced MET, with the increased expression of epithelial markers (KRT8, KRT18, KRT7) and a reduction in ZEB1/2 mesenchymal markers. FN1, another mesenchymal marker, was also observed to be down-regulated (at both the mRNA and protein levels) in cells transfected with miR-200b, miR-200c and miR-429 [104]. When comparing exosomes originating from two ovarian cancer cell lines with high invasion potential (SKOV-3) and low invasion potential (OVCAR-3), Kobayashi et al. [105] discovered differences between the number of released exosomes and the expression of let-7 and miR-200 family members. While the let-7 family transcripts (let-7a-f) were up-regulated in exosomes of the SKOV-3 cells, miR-200 family members were expressed only in the OVCAR-3 cells and their exosomes [105].

The investigation of clinical data based on samples from patients with ovarian cancer revealed the dysregulated expression of miR-200c. Pivotal studies that focused on tissues have identified miR-200c as comprising one of the most elevated miRNAs. Iorio et al. [53] determined that miR-200c along with other members of the miR-200 family comprise the most upregulated miRNA of the three histotypes investigated (serous, endometrioid and clear cell). Subsequent reports indicated the upregulation of miR-200c in ovarian cancer [25, 106, 107, 108]. A growing body of evidence also indicates differences between the various miR-200 family members in terms of their expression, presumed roles in carcinogenesis and association with the outcomes of patients. Regarding the latter, due to the publication of conflicting results, the issue remains open to question. The data available implies that the biological functions and the alterations in the expression of the miR-200 family are subject to changes and may depend on the cellular context, the stage of tumor progression and metastasis, and the nuclear or cytoplasmic localization of the interacting targets. This may explain why miR-200 family members have been identified as both tumor suppressors and oncogenes in cancer [109]. Moreover, the various members of the miR-200 family appear to differ in terms of their expression alterations. For example, Marchini et al. [110] compared the expression of miRNAs between tumors in relapsers and non-relapsers. Interestingly, the levels of miR-200c in the tumors were observed to be elevated in the non-relapsers, while miR-200b was upregulated in the relapsers versus the non-relapsers. Moreover, the higher expression of miR-200c was associated with improved overall survival and progression-free survival. Prislei et al. [111] identified a multidimensional miRNA regulation pattern while poor or good outcomes correlated to the cellular localization of HuR. The nuclear localization of HuR and the high miR-200c expression acted to inhibit TUBB3 and resulted in favorable outcomes. Conversely, poor outcomes were observed when HuR occurred in cytoplasm and miR-200c enhanced the expression of TUBB3. In another study, high miR-200c-3p expression was associated with poor progression-free and overall survival in high-grade serous ovarian carcinoma patients [91]. The increased expression of miR-200c has been associated with favorable outcomes for patients based on the metanalysis of 15 studies on ovarian cancer [112]. Interestingly, the opposite pattern, i.e. the association of higher levels of miR-200c with worse survival rates has been identified based on the results of 58 research articles on various cancer types [109]. Conversely, with respect to ovarian cancer, Gao et al. [113] observed a descending trend in miR-200c expression levels from the early stages to the advanced stages associated with a lower 2-year survival rate in the latter group.

Ibrahim et al. [114] determined miR-200c to be most upregulated in tissues in cases where there is evidence of metastasis. Experimental transfection using miR-200c mimics or inhibitors has demonstrated that overexpressed miR-200c acted to enhance cell proliferation and colony formation, but served to reduce the migration and invasion of ovarian cancer cells. The inhibition of miR-200c resulted in the opposite pattern [114].

Elevated miR-200c serum levels have also been observed [115] in connection with disease progression [116], even when using the exosomal serum fraction [117]. Low levels of plasma miR-200c have been associated with the 5-month prolongation of PFS when treated with bevacizumab compared to standard chemotherapy [118].

Several reports based on cell lines have suggested that miR-200c may enhance sensitivity to chemotherapy [100, 119, 120, 121, 122] or inhibit tumorigenicity and metastasis [123]. Recently, it has been determined that the upregulation of miR-200b and miR-200c may enhance the sensitivity of cancer cells to cisplatin, in addition to the finding that miR-200b and miR-200c were downregulated in ovarian tumors compared with normal tissues [100].

4. Conclusion

Establishing particular miRNAs as novel reliable biomarkers remains the goal of current research in the field of ovarian cancer; however, the research faces a number of important challenges, particularly in connection with the inconsistency of the data. Further studies and the integration of the results thereof are required in order to overcome these challenges and the various research pitfalls and to elucidate the fundamental roles of microRNAs in the initiation and progression of ovarian cancer. The various methodological challenges, e.g. limited sample numbers, sample heterogeneity, differing sample collection platforms, the various approaches to the analysis of expression including normalization, ethno-geographical factors and the artificial effects of cell lines involving cross-contamination and misidentification (e.g., [124]) often act to negatively affect the consistency of the research results.

Any ascites-based miRNA research may have its advantages and drawbacks introduced by a variety of factors. The type of studied material and a selection of appropriate controls are generally the principal sources of bias. Several authors included ascites-derived cancer cells as the primary object of their investigation [16, 20]. However, unsorted preparation of cell pellets represents a variable mixture of cells from different tissues with likely consequence on the results. Cancer cells (a limit used in the abovementioned studies is more than 50%), reactive mesothelial cells and leukocytes may occur at highly variable proportions as well as absolute counts. Exosome or extracellular vesicle fractions of ascites represents another type of material studied [18, 19]. It is, nevertheless, also a heterogeneous entity that includes different vesicle subtypes of various origins. Furthermore, no consensus has been reached with respect to their isolation, content and purity evaluation, yet. Another miRNAs source may be the whole extracellular fraction of ascites, which contains non-coding RNAs from cells and other components derived from tumor or blood (e.g., white and red blood cells, platelets, extracellular vesicles) that may release variable miRNAs. The choice of appropriate control is also challenging. Reactive mesothelial cells from benign ascites may serve as a control for cancer cells, while plasma or serum from healthy subjects can be used for comparison with whole cell-free ascites. However, benign diseases may affect miRNA profile, and specific miRNAs altering the expression profiles may be released upon hemolysis often occurring in plasma/serum/ascites samples.

Due to technical challenges, most studies analyzed samples without detailed characterization of the origin of the miRNome. Additionally, technical differences in sample collection, processing and normalization, together with low patients’ numbers and highly variable nature of ovarian cancer significantly increase heterogeneity of the results among different studies. Nevertheless, the evaluation of the ascites-derived miRNA expression based on different and independent platforms may provide valuable insight into tumor miRNA deregulations that could contribute to our better understanding of development, progression or treatment response of ovarian cancer.

With respect to carcinogenesis, various hallmark processes have been identified as participating in the promotion of cancer [125] that affect not only the site of origin but also other parts of the body including the circulation system. The differing body fluids that have been identified as the source of circulating miRNAs [126] may reflect the various states of the disease and the changes that occur at different locations and times. miRNAs can be altered by several factors that ultimately affect the regulation of their target mRNAs. A large number of miRNA target genes/mRNAs are able to act as oncogenes or tumor suppressors and, moreover, a single miRNA is able to regulate several mRNAs while a single mRNA can be regulated by multiple miRNAs [12]. The biological roles of miRNAs are extremely complex and, particularly in diseased states such as cancer, it is difficult to draw conclusions based merely on one sample type.

The analysis of the expression of miRNAs has tended to employ samples from heterogeneous origins. Ovarian tumor tissues are complex entities with respect both to the various histological/molecular subtypes and the tumor itself (e.g. [127]). Tumors contain not only true cancer cells of various types including stem cells but also vascular components and elements of the immune system such as tumor infiltrating lymphocytes, all of which contain their own miRNAs. The complex nature of the blood and its related liquids (plasma/serum/ascites) is reflected by the various components that release miRNAs (white and red blood cells and platelets) and, partially, by the released tumor cells that potentially participate in the spread of cancer within the body [128, 129].

This review identified several miRNAs with common alterations in terms of their expression in ascites. We focused on four potential tumor suppressor miRNAs and three potential oncogenic miRNAs involved in ovarian cancer that differ in terms of their function and outcomes in clinical observations. A strong body of evidence supports the view of let-7b and miR-143 as tumor suppressors in line with the data on other cancer types. Contrasting results were determined for miR-26a and miR-145 with respect to their dominant role as tumor suppressing miRNAs and their occasional exhibiting of oncogenic roles in ovarian cancer. The result of the consideration of miR-95-3p, which is upregulated in ascites, was inconclusive due to the lack of data with respect to ovarian cancer despite the reporting of its oncogenic role in other cancers. Contrasting findings were also reported for miR-182-5p and miR-200c; in addition to their presumed oncogenic roles, findings have also indicated their ambivalent functions in ovarian cancer.

The findings thus suggest that miRNAs play complex and often contradictory roles in ovarian carcinogenesis. However, many miRNAs are promissing candidates for further research. Ascites as a fluid rich in biologically active constituents provides promising potential for the evaluation of biomarkers within the miRNOme and other non-coding RNA-ome. MicroRNA profiling is currently not recommended in routine clinical care due to numerous and challenging obstacles (some of them noted above) while many novel diagnostic, prognostic or screening panels are being developed (e.g. [130, 131, 132]). The utilization of different miRNAs in common clinical practice will increase, when sufficient evidence is accumulated on their role in carcinogenesis as well as their diagnostic or predictive performance. Future findings may also allow development of innovative treatment options that would target miRNOme in ovarian cancer. As the clinical investigations focused on ascites-based miRNAs are relatively neglected, testing larger patients cohorts in multiple independent studies including more and newly discovered miRNAs would be necessary to obtain a more comprehensive view of their biological functions.

Author contributions

Conception: LZ.

Interpretation or analysis of data: LZ, EJ, VW, VH, OS, MK.

Preparation of the manuscript: LZ.

Revision for important intellectual content: LZ, EJ, VW, VH, OS, MK.

Supervision: LZ, OS, MK.

Supplementary data

The supplementary files are available to download from http://dx.doi.org/10.3233/CBM-210219.

sj-docx-1-cbm-10.3233_CBM-210219.docx - Supplemental material

Supplemental material, sj-docx-1-cbm-10.3233_CBM-210219.docx

Footnotes

Acknowledgments

This work was financially supported by Charles University, Prague (Progres Q28/LF1, Progres Q25/LF1) and Ministry of Health of the Czech Republic (CZ-DRO FNBr 65269705).

Conflict of interest

None declared

References

Sung

Ferlay

Siegel

R.L.

Laversanne

et al., Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA: A Cancer Journal for Clinicians 71(3) (2021), 209–249.

Matz

Coleman

M.P.

Carreira

et al., Worldwide comparison of ovarian cancer survival: Histological group and stage at diagnosis (CONCORD-2), Gynecologic Oncology 144 (2017), 396–404.

Wei

Sun

et al., Clinical outcome and prognostic factors of patients with earlystage epithelial ovarian cancer, Oncotarget 8 (2017), 23862–70.

Puls

L.E.

Duniho

Hunter

J.E.

et al., The prognostic implication of ascites in advanced-stage ovarian cancer, Gynecologic Oncology 61 (1996), 109–12.

Quan

Zhou

Liu

et al., Relationship between ascites volume and clinical outcomes in epithelial ovarian cancer, Journal of Obstetrics and Gynaecology Research (2021). doi: 10.1111/jog.14682.

Ahmed

and Stenvers

K.L.

, Getting to know ovarian cancer ascites: Opportunities for targeted therapy-based translational research, Frontiers in Oncology 3 (2013), 256.

Shender

V.O.

Pavlyukov

M.S.

Ziganshin

R.H.

et al., Proteome-metabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication, Molecular and Cellular Proteomics 13 (2014), 3558–71.

Foord

Arruda

Gaballa

et al., Characterization ofascites- and x tumor-infiltratinggamma delta T cells reveals distinct repertoires and a beneficial role in ovarian cancer, Science Translational Medicine 13(577) (2021), eabb0192.

Kipps

Tan

D.S.P.

and Kaye

S.B.

, Meeting the challenge of ascites in ovarian cancer: New avenues for therapy and research, Nature Reviews Cancer 13 (2013), 273–82.

10.

Cohen

and Petignat

, The bright side of ascites in ovarian cancer, Cell Cycle 13 (2014), 2319.

11.

Kotrbova

Ovesna

Gybel

et al., WNT signaling inducing activity in ascites predicts poor outcome in ovarian cancer, Theranostics 10 (2020), 537–52.

12.

Iorio

M.V.

and Croce

C.M.

, MicroRNA dysregulation in cancer: Diagnostics, monitoring and therapeutics. A comprehensive review, EMBO Molecular Medicine 4 (2012), 143–59.

13.

Steidel

Ender

Rody

et al., Biologically active tissue factor-bearing larger ectosome-like extracellular vesicles in malignant effusions from ovarian cancer patients: Correlation with incidence of thrombosis, International Journal of Molecular Sciences 22 (2021), 1–10.

14.

Mutlu

Raza

Saatci

et al., miR-200c: a versatile watchdog in cancer progression, EMT, and drug resistance, Journal of Molecular Medicine 94 (2016), 629–44.

15.

van Jaarsveld

M.T.M.

Helleman

Berns

E.M.J.J.

and Wiemer

E.A.C.

, MicroRNAs in ovarian cancer biology and therapy resistance, International Journal of Biochemistry and Cell Biology 42 (2010), 1282–90.

16.

Vaksman

Stavnes

H.T.

Kaern

et al., miRNA profiling along tumour progression in ovarian carcinoma, Journal of Cellular and Molecular Medicine 15 (2011), 1593–602.

17.

Chung

Y.W.

Bae

H.S.

Song

J.Y.

et al., Detection of microRNA as novel biomarkers of epithelial ovarian cancer from the serum of ovarian cancer patient, International Journal of Gynecological Cancer 23 (2013), 673–9.

18.

Cappellesso

Tinazzi

Giurici

et al., Programmed cell death 4 and microRNA 21 inverse expression is maintained in cells and exosomes from ovarian serous carcinoma effusions, Cancer Cytopathology 122 (2014), 685–93.

19.

Vaksman

Trope

Davidson

and Reich

, Exosome-derived miRNAs and ovarian carcinoma progression, Carcinogenesis 35 (2014), 2113–20.

20.

Nymoen

D.A.

Slipicevic

Holth

et al., MiR-29a is a candidate biomarker of better survival in metastatic high-grade serous carcinoma, Human Pathology 54 (2016), 74–81.

21.

Zavesky

Jandakova

Weinberger

et al., Ascites-Derived Extracellular microRNAs as Potential Biomarkers for Ovarian Cancer, Reproductive Sciences 26 (2019), 510–22.

22.

Zavesky

Jandakova

Weinberger

et al., Ovarian cancer: differentially expressed micrornas in tumor tissue and cell-free ascitic fluid as potential novel biomarkers, Cancer Investigation 37 (2019), 440–52.

23.

Lucidi

Buca

Ronsini

et al., Role of extracellular vesicles in epithelial ovarian cancer: A systematic review, International Journal of Molecular Sciences 21 (2020), 1–16.

24.

Yamamoto

C.M.

Oakes

M.L.

Murakami

et al., Comparison of benign peritoneal fluid- and ovarian cancer ascites-derived extracellular vesicle RNA biomarkers, Journal of Ovarian Research 11 (2018), Article Number: 20.

25.

Nam

E.J.

Yoon

Kim

S.W.

et al., MicroRNA expression profiles in serous ovarian carcinoma, Clinical Cancer Research 14 (2008), 2690–5.

26.

Yang

Kong

et al., MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistence by targeting PTEN, Cancer Res 68(2) (2008), 425–433.

27.

Tang

G.S.

Thiery

J.P.

et al., Meta-analysis of transcriptome reveals let-7b as an unfavorable prognostic biomarker and predicts molecular and clinical subclasses in high-grade serous ovarian carcinoma, International Journal of Cancer 134 (2014), 306–18.

28.

Kuang

et al., Inhibition of microRNA let-7b expression by KDM2B promotes cancer progression by targeting EZH2 in ovarian cancer, Cancer Science 112 (2021), 231–42.

29.

Zheng

et al., MicroRNA let-7b inhibits cell proliferation via upregulation of p21 in hepatocellular carcinoma, Cell and Bioscience 10(1) (2020), Article Number: 83.

30.

Wang

et al., Let-7b contributes to hepatocellular cancer progression through Wnt/+–catenin signaling, Saudi Journal of Biological Sciences 25 (2018), 953–8.

31.

Han

Zhang

J.J.

Han

Z.Q.

et al., Let-7b attenuates cisplatin resistance and tumor growth in gastric cancer by targeting AURKB, Cancer Gene Therapy 25 (2018), 300–8.

32.

Huang

Wang

et al., MicroRNA let-7b Inhibits Proliferation and Induces Apoptosis of Castration-Resistant Prostate Cancer Cells by Blocking the Ras/Rho Signaling Pathway via NRAS, Clinical and Translational Science (2020). doi: 10.1111/cts.12743.

33.

N.H.

Wei

C.Y.

F.Z.

and Gu

J.Y

, Hsa-let-7b Suppresses Cell Proliferation by Targeting UHRF1 in Melanoma, Cancer Investigation 38 (2020), 52–60.

34.

Gao

Bian

et al., MiR-26a inhibits ovarian cancer cell proliferation, migration and invasion by targeting TCF12, Oncology Reports 43 (2020), 368–74.

35.

Sun

T.Y.

Xie

H.J.

et al., miR-26a inhibits the proliferation of ovarian cancer cells via regulating CDC6 expression, American Journal of Translational Research 8 (2016), 1037–46.

36.

Shen

Song

Liu

et al., MiR-26a promotes ovarian cancer proliferation and tumorigenesis, PLoS ONE 9(1) (2014), Article Number: e86871.

37.

Wei

Chang

Fan

and Zhang

, MiR-26a/miR-26b represses tongue squamous cell carcinoma progression by targeting PAK1, Cancer Cell International 20(1) (2020), Article Number: 82.

38.

and Chen

, MiRNA-26a blocks interleukin-2-mediated migration and proliferation of non-small cell lung cancer cells via vascular cell adhesion molecule-1, Translational Cancer Research 9 (2020), 1768–78.

39.

Zhu

W.J.

Yan

Zhang

J.W.

et al., Effect and mechanism of mir-26a-5p on proliferation and apoptosis of hepatocellular carcinoma cells, Cancer Management and Research 12 (2020), 3013–22.

40.

Zhao

W.T.

Lin

X.L.

Liu

et al., miR-26a promotes hepatocellular carcinoma invasion and metastasis by inhibiting PTEN and inhibits cell growth by repressing EZH2, Laboratory Investigation 99 (2019), 1484–500.

41.

Yuan

Y.L.

S.M.

et al., MiR-26a-5p Inhibits Cell Proliferation and Enhances Doxorubicin Sensitivity in HCC Cells via Targeting AURKA, Technology in Cancer Research & Treatment 18 (2019), Article Number: 1533033819851833.

42.

Deng

et al., The tumor suppressive miR-26a regulation of FBXO11 inhibits proliferation, migration and invasion of hepatocellular carcinoma cells, Biomedicine and Pharmacotherapy 101 (2018), 648–55.

43.

Jiang

and Yang

, Targeted regulation of mir-26a on pten to affect proliferation and apoptosis of prostate cancer cells, Cancer Biotherapy and Radiopharmaceuticals 34 (2019), 480–5.

44.

Huang

Z.M.

H.F.

Yang

C.C.

et al., MicroRNA-26a-5p inhibits breast cancer cell growth by suppressing RNF6 expression, Kaohsiung Journal of Medical Sciences 35 (2019), 467–73.

45.

Yin

Wang

et al., Serum miR-26a/b expression correlates with pathological features in patients with gastric cancer, International Journal of Clinical and Experimental Medicine 13 (2021), 893–900.

46.

Coronel-Hernandez

Lopez-Urrutia

Contreras-Romero

et al., Cell migration and proliferation are regulated by miR-26a in colorectal cancer via the PTEN-AKT axis, Cancer Cell International 19 (2019), Article Number 80.

47.

Cai

Guan

Wang

et al., MicroRNA-26a regulates ANXA1, rather than DAL-1, in the development of lung cancer, Oncology Letters 15 (2018), 5893–902.

48.

Zhou

Wei

Shi

et al., miR-26a inhibits cell proliferation and induces apoptosis in human bladder cancer through regulating EZH2 bioactivity, International Journal of Clinical and Experimental Pathology 10 (2017), 11234–41.

49.

Zhong

Yao

Zhao

and Zhang

, MiR-26a suppresses the growth and metastasis via targeting matrix metalloproteinase 14 in pancreatic ductal adenocarcinoma, International Journal of Clinical and Experimental Pathology 9 (2016), 4803–9.

50.

Dong

Sui

Wang

et al., MicroRNA-26a inhibits cell proliferation and invasion of cervical cancer cells by targeting protein tyrosine phosphatase type IVA 1, Molecular Medicine Reports 10 (2014), 1426–32.

51.

Reuland

S.N.

Smith

S.M.

Bemis

L.T.

et al., MicroRNA-26a is strongly downregulated in melanoma and induces cell death through repression of silencer of death domains (SODD), Journal of Investigative Dermatology 133 (2013), 1286–93.

52.

Zhang

et al., miR-26a inhibits invasion and metastasis of nasopharyngeal cancer by targeting EZH2, Oncology Letters 5 (2013), 1223–8.

53.

Iorio

M.V.

Visone

Di Leva

et al., MicroRNA signatures in human ovarian cancer, Cancer Research 67 (2007), 8699–707.

54.

Xiao

Wang

et al., MiR-145 is downregulated in human ovarian cancer and modulates cell growth and invasion by targeting p70S6K1 and MUC1, Biochemical and Biophysical Research Communications 441 (2013), 693–700.

55.

Zhu

Xie

et al., MiR-145 sensitizes ovarian cancer cells to paclitaxel by targeting Sp1 and Cdk6, International Journal of Cancer 135 (2014), 1286–96.

56.

Zhang

Wang

et al., MicroRNA-145 function as a cell growth repressor by directly targeting c-Myc in human ovarian cancer, Technology in Cancer Research and Treatment 13 (2014), 161–8.

57.

Dong

Liu

Zhang

et al., miR-145 inhibits tumor growth and metastasis by targeting metadherin in high-grade serous ovarian carcinoma, Oncotarget 5 (2014), 10816–29.

58.

Kim

T.H.

Song

J.Y.

Park

et al. carcinoma

MiR-145,targetinghigh-mobilitygroupA2,isapowerfulpredictorofpatientoutcomeinovarian

, Cancer Letters 356 (2015), 937–45.

59.

Chen

Dong

Law

P.T.Y.

et al., MicroRNA-145 targets TRIM2 and exerts tumor-suppressing functions in epithelial ovarian cancer, Gynecologic Oncology 139 (2015), 513–9.

60.

Wang

et al., Mechanisms of miR-145 regulating invasion and metastasis of ovarian carcinoma, American Journal of Translational Research 9 (2017), 3443–51.

61.

Hua

Qin

Sheng

et al., MiR-145 suppresses ovarian cancer progression via modulation of cell growth and invasion by targeting CCND2 and E2F3, Molecular Medicine Reports 49 (2019), 3575–83.

62.

Zhou

Zhang

and Chen

, MicroRNA-145-5p regulates the proliferation of epithelial ovarian cancer cells via targeting SMAD4, Journal of Ovarian Research 13(1) (2020), Article Number: 54.

63.

Pei

and Zhang

, YTHDF2, a protein repressed by miR-145, regulates proliferation, apoptosis, and migration in ovarian cancer cells, Journal of Ovarian Research 13(1) (2020), Article Number: 111.

64.

Wang

Fang

et al., Identification of microRNAs and target genes involved in serous ovarian carcinoma and their influence on survival, European Journal of Gynaecological Oncology 35 (2014), 655–61.

65.

Kim

T.H.

Song

J.Y.

Park

et al., miR-145, targeting high-mobility group A2, is a powerful predictor of patient outcome in ovarian carcinoma, Cancer Letters 356(2) (2015), 937–945.

66.

Liang

Jiang

Xie

and Lu

, Serum microRNA-145 as a novel biomarker in human ovarian cancer, Tumor Biology 36 (2015), 5305–13.

67.

Wang

Yin

Shan

et al., The Value of Plasma-Based MicroRNAs as Diagnostic Biomarkers for Ovarian Cancer, American Journal of the Medical Sciences 358 (2019), 256–67.

68.

Kim

Choi

M.C.

Jeong

J.Y.

et al., Serum exosomal miRNA-145 and miRNA-200c as promising biomarkers for preoperative diagnosis of ovarian carcinomas, Journal of Cancer 10 (2019), 1958–67.

69.

Shen

Weng

et al., Low miR-145 silenced by DNA methylation promotes NSCLC cell proliferation, migration and invasion by targeting mucin 1, Cancer Biology and Therapy 16 (2015), 1071–9.

70.

Zhao

Kang

Xia

et al., miR-145 suppresses breast cancer cell migration by targeting FSCN-1 and inhibiting epithelial-mesenchymal transition, American Journal of Translational Research 8 (2016), 3106–14.

71.

Khan

Ebeling

M.C.

Zaman

M.S.

et al., MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer, Oncotarget 5 (2014), 7599–609.

72.

Han

Liu

Zhou

et al., The negative feedback between miR-143 and DNMT3A regulates cisplatin resistance in ovarian cancer, Cell Biology International 45 (2021), 227–37.

73.

Zhai

, Lncrna CDKN2B-AS1 promotes the progression of ovarian cancer by MiR-143-3p/SMAD3 axis and predicts a poor prognosis, Neoplasma 67 (2020), 782–93.

74.

Wen

Han

Cui

and Wang

, Long non-coding RNA MCM3AP-AS1 drives ovarian cancer progression via the microRNA-143-3p/TAK1 axis, Oncology Reports 44 (2020), 1375–84.

75.

Niu

Qin

et al., lncRNA UCA1 Mediates Resistance to Cisplatin by Regulating the miR-143/FOSL2-Signaling Pathway in Ovarian Cancer, Molecular Therapy – Nucleic Acids 17 (2019), 92–101.

76.

Lin

Guan

Ren

et al., MALAT1 affects ovarian cancer cell behavior and patient survival, Oncology Reports 39 (2018), 2644–52.

77.

Guan

Wang

Lin

et al., Transforming growth factor-beta/miR-143-3p/cystatin B axis is a therapeutic target in human ovarian cancer, International Journal of Oncology 55 (2019), 267–76.

78.

Shi

Shen

et al., MiR-143-3p suppresses the progression of ovarian cancer, American Journal of Translational Research 10 (2018), 866–74.

79.

Zhang

and Li

, Dysregulation of micro-143-3p and BALBP1 contributes to the pathogenesis of the development of ovarian carcinoma, Oncology Reports 36 (2016), 3605–10.

80.

Wang

et al., MiR-143 targets CTGF and exerts tumor-suppressing functions in epithelial ovarian cancer, American Journal of Translational Research 8 (2016), 2716–26.

81.

Guo

Sun

et al., MicroRNA-143-3p inhibits colorectal cancer metastases by targeting ITGA6 and ASAP3, Cancer Science 110 (2019), 805–16.

82.

Sanada

Seki

Mizuno

et al., Involvement of dual strands of miR-143 (miR-143-5p and miR-143-3p) and their target oncogenes in the molecular pathogenesis of lung adenocarcinoma, International Journal of Molecular Sciences (2019), 20.

83.

Huang

Wang

et al., MicroRNA-95 promotes cell proliferation and targets sorting nexin 1 in human colorectal carcinoma, Cancer Research 71 (2011), 2582–9.

84.

Qin

Teng

J.A.

Zhu

et al., Glargine Promotes Human Colorectal Cancer Cell Proliferation via Upregulation of miR-95, Hormone and Metabolic Research 47 (2015), 861–5.

85.

Qin

Chen

J.X.

Zhu

and Teng

J.A.

, Genistein inhibits human colorectal cancer growth and suppresses MiR-95, Akt and SGK1, Cellular Physiology and Biochemistry 35 (2015), 2069–77.

86.

Zhao

Ren

et al., Calycosin induces apoptosis in colorectal cancer cells, through modulating the ER+-/MiR-95 and IGF-1R, PI3K/Akt signaling pathways, Gene 592 (2016), 123–8.

87.

Chen

et al., Clinical characteristics of colorectal cancer patients and anti-neoplasm activity of genistein, Biomedicine and Pharmacotherapy 124 (2020), Article Number: 109835.

88.

Zhuang

Tan

et al., microRNA-95 knockdown inhibits epithelial-mesenchymal transition and cancer stem cell phenotype in gastric cancer cells through MAPK pathway by upregulating DUSP5, Journal of Cellular Physiology 235 (2020), 944–56.

89.

Cheng

Hua

et al., MicroRNA-95-3p promoted the development of prostatic cancer via regulating DKK3 and activating Wnt/+–catenin pathway, European Review for Medical and Pharmacological Sciences 23 (2019), 1002–11.

90.

Hong

Y.G.

Huang

Z.P.

Liu

Q.Z.

et al., MicroRNA-95-3p inhibits cell proliferation and metastasis in colorectal carcinoma by HDGF, Biomedical Journal 43 (2020), 163–73.

91.

Elgaaen

Olstad

O.K.

Haug

K.B.F.

et al., Global miRNA expression analysis of serous and clear cell ovarian carcinomas identifies differentially expressed miRNAs including miR-200c-3p as a prognostic marker, BMC Cancer 14 (2014), Article Number: 80.

92.

Wang

Zhu

M.J.

Ren

A.M.

et al., A ten-microRNA signature identified from a genome-wide microRNA expression profiling in human epithelial ovarian cancer, PLoS ONE 9(5) (2014), Article Number: e96472.

93.

Marzec-Kotarska

Cybulski

Kotarski

J.C.

et al., Molecular bases of aberrant miR-182 expression in ovarian cancer, Genes Chromosomes and Cancer 55 (2016), 877–89.

94.

Wang

Jin

et al., LncRNA ADAMTS9-AS2 regulates ovarian cancer progression by targeting miR-182-5p/FOXF2 signaling pathway, International Journal of Biological Macromolecules 120 (2018), 1705–13.

95.

Wang

Cao

Q.X.

Tian

et al., Circular RNA MTO1 Inhibits the Proliferation and Invasion of Ovarian Cancer Cells Through the miR-182-5p/KLF15 Axis, Cell Transplantation 29 (2020), Article Number: 0963689720943613.

96.

Duan

Yan

Wang

et al., miR-182-5p functions as a tumor suppressor to sensitize human ovarian cancer cells to cisplatin through direct targeting the cyclin dependent kinase 6 (CDK6), Journal of BUON 25 (2020), 2279–86.

97.

Yan

Wang

Chen

et al., MiR-182-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-C, Cancer Letters 488 (2020), 18–26.

98.

Gao

Yan

S.B.

Yang

et al., MiR-182-5p and its target HOXA9 in non-small cell lung cancer: A clinical and in-silico exploration with the combination of RT-qPCR, miRNA-seq and miRNA-chip, BMC Medical Genomics 13(1) (2020), Article Number: 3.

99.

Dahiya

Sherman-Baust

C.A.

Wang

T.L.

et al., MicroRNA expression and identification of putative miRNA targets in ovarian cancer, PLoS ONE 3(6) (2008), Article Number: e2436.

100.

Liu

Zhang

Huang

et al., mir-200b and mir-200c co-contribute to the cisplatin sensitivity of ovarian cancer cells by targeting DNA methyltransferases, Oncology Letters 17 (2019), 1453–60.

101.

Humphries

and Yang

, The microRNA-200 family: Small molecules with novel roles in cancer development, progression and therapy, Oncotarget 6 (2015), 6472–98.

102.

Teng

Zhang

et al., miRNA-200a/c as potential biomarker in epithelial ovarian cancer (EOC): evidence based on miRNA meta-signature and clinical investigations, Oncotarget 7(49) (2016), 81621–81633.

103.

Bendoraite

Knouf

E.C.

Garg

K.S.

et al., Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: Evidence supporting a mesothelial-to-epithelial transition, Gynecologic Oncology 116 (2010), 117–25.

104.

Jabbari

Reavis

A.N.

and McDonald

J.F.

, Sequence variation among members of the miR-200 microRNA family is correlated with variation in the ability to induce hallmarks of mesenchymal-epithelial transition in ovarian cancer cells, Journal of Ovarian Research 7 (2014), Article Number: 12.

105.

Kobayashi

Salomon

Tapia

et al., Ovarian cancer cell invasiveness is associated with discordant exosomal sequestration of Let-7 miRNA and miR-200, Journal of Translational Medicine 12 (2014), Article Number: 4

106.

Taylor

D.D.

and Gercel-Taylor

, MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer, Gynecologic Oncology 110 (2008), 13–21.

107.

Wyman

S.K.

Parkin

R.K.

Mitchell

P.S.

et al., Repertoire of microRNAs in epithelial ovarian cancer as determined by next generation sequencing of small RNA cDNA libraries, PLoS ONE 4(4) (2009), Article Number: e5311.

108.

Cao

Dai

et al., Clinicopathological and prognostic implications of the miR-200 family in patients with epithelial ovarian cancer, International Journal of Clinical and Experimental Pathology 7 (2014), 2392–401.

109.

Huang

G.L.

Sun

et al., MiR-200 family and cancer: From a meta-analysis view, Molecular Aspects of Medicine 70 (2019), 57–71.

110.

Marchini

Cavalieri

Fruscio

et al., Association between miR-200c and the survival of patients with stage I epithelial ovarian cancer: A retrospective study of two independent tumour tissue collections, The Lancet Oncology 12 (2011), 273–85.

111.

Prislei

Martinelli

Mariani

et al., MiR-200c and HuR in ovarian cancer, BMC Cancer 13 (2013), Article Number: 72

112.

Shi

Zhang

et al., MicroRNA-200 and microRNA-30 family as prognostic molecular signatures in ovarian cancer: A meta-analysis, Medicine (United States) 97(32) (2018), Article Number: e11505.

113.

Gao

Y.C.

and Wu

, MicroRNA-200c and microRNA-141 as potential diagnostic and prognostic biomarkers for ovarian cancer, Tumor Biology 36 (2015): 4843–50.

114.

Ibrahim

F.F.

Jamal

Syafruddin

S.E.

et al., MicroRNA-200c and microRNA-31 regulate proliferation, colony formation, migration and invasion in serous ovarian cancer, Journal of Ovarian Research 8 (2015), Article Number: 56.

115.

Kan

C.W.S.

Hahn

M.A.

Gard

G.B.

et al., Elevated levels of circulating microRNA-200 family members correlate with serous epithelial ovarian cancer, BMC Cancer 12 (2012), Article Number: 627.

116.

Zuberi

Mir

Das

et al., Expression of serum miR-200a, miR-200b, and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features, Clinical and Translational Oncology 17 (2015), 779–87.

117.

Meng

Muller

Milde-Langosch

et al., Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer, Oncotarget 7 (2016), 16923–35.

118.

Halvorsen

A.R.

Kristensen

Embleton

et al., Evaluation of prognostic and predictive significance of circulating MicroRNAs in ovarian cancer patients, Disease Markers 2017 (2017), Article Number: 3098542.

119.

Cittelly

D.M.

Dimitrova

Howe

E.N.

et al., Restoration of miR-200c to ovarian cancer reduces tumor burden and increases sensitivity to paclitaxel, Molecular Cancer Therapeutics 11 (2012), 2556–65.

120.

Brozovic

Duran

G.E.

Wang

Y.C.

et al., The miR-200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR-3 and MES-OV cells, Molecular Oncology 9 (2015), 1678–93.

121.

Wang

Chen

Shi

et al., MiR-200c inhibits HOTAIR expression resulting in the decrease of chemoresistance in ovarian cancer stem cells, International Journal of Clinical and Experimental Medicine 9 (2016), 13783–92.

122.

Vescarelli

Gerini

Megiorni

et al., MiR-200c sensitizes Olaparib-resistant ovarian cancer cells by targeting Neuropilin 1, Journal of Experimental and Clinical Cancer Research 39(1) (2020), Article Number: 3.

123.

Chen

Zhang

Wang

et al., MicroRNA-200c overexpression inhibits tumorigenicity and metastasis of CD117+CD44+ ovarian cancer stem cells by regulating epithelial-mesenchymal transition, Journal of Ovarian Research 6 (2013), Article Number: 50.

124.

Huang

Liu

Zheng

and Shen

, Investigation of cross-contamination and misidentification of 278 widely used tumor cell lines, PLoS ONE 12(1) (2017), Article Number: e0170384.

125.

Hanahan

and Weinberg

R.A.

, Hallmarks of cancer: The next generation, Cell 144 (2011), 646–74.

126.

Weber

J.A.

Baxter

D.H.

Zhang

S.L.

et al., The MicroRNA Spectrum in 12 Body Fluids 13, Clinical Chemistry 56 (2010), 1733–41.

127.

Geistlinger

Ramos

et al., Multiomic analysis of subtype evolution and heterogeneity in high-grade serous ovarian carcinoma, Cancer Research 80 (2021), 4335–45.

128.

Zavesky

Jandakova

Turyna

et al., New perspectives in diagnosis of gynaecological cancers: Emerging role of circulating microRNAs as novel biomarkers, Neoplasma 62 (2015), 509–20.

129.

Banys-Paluchowski

Fehm

Neubauer

et al., Clinical relevance of circulating tumor cells in ovarian, fallopian tube and peritoneal cancer, Archives of Gynecology and Obstetrics 301 (2020), 1027–35.

130.

Yokoi

Matsuzaki

Yamamoto

et al., Integrated extracellular microRNA profiling for ovarian cancer screening, Nature Communications 9(2018), Article Number: 4319.

131.

Krasniqi

Sacconi

Marinelli

et al., MicroRNA-based signatures impacting clinical course and biology of ovarian cancer: a miRNOmics study, Biomarker Research 9 (2021), Article number: 57.

132.

Sathipati

S.Y.

, Identification of the miRNA signature associated with survival in patients with ovarian cancer, Aging-US 13(9) (2021), 12660–12690.

Ascites in ovarian cancer: MicroRNA deregulations and their potential roles in ovarian carcinogenesis

Abstract

Keywords

1. Introduction

2. Ascites as the source of biomarkers for ovarian cancer

2.1 Cellular fractions of ascites

Table 1 Differential expression of microRNAs in various types of ascites-derived samples associated with ovarian cancer

2.3 Whole extracellular fractions of ascites

3. Expression pattern of ascites-derived miRNAs in ovarian cancer

3.1 Potential tumor suppressor miRNAs let-7b, miR-26a, miR-145 and miR-143, and potential oncogenic miRNAs miR-95-3p, miR-182-5p and miR-200c-3p in focus

3.1.1 Let-7b

3.1.2 miR-26a ( = miR-26a-5p)

3.1.3 miR-145 ( = miR-145-5p)

3.1.4 miR-143 ( = miR-143-3p)

3.1.5 miR-95 ( = miR-95-3p)

3.1.6 miR-182-5p

3.1.7 miR-200c-3p

4. Conclusion

Author contributions

Supplementary data

sj-docx-1-cbm-10.3233_CBM-210219.docx - Supplemental material

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Differential expression of microRNAs in various types of ascites-derived samples associated with ovarian cancer

3.1.2 miR-26a ( $=$ miR-26a-5p)

3.1.3 miR-145 ( $=$ miR-145-5p)

3.1.4 miR-143 ( $=$ miR-143-3p)

3.1.5 miR-95 ( $=$ miR-95-3p)