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Abstract

BACKGROUND:

Plasma carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4) are common markers which are useful in the diagnosis and prognosis of GC. However, their sensitivity and specificity in GC remain unsatisfactory. Identification of cancer diagnosed-biomarkers would be of great value.

OBJECTIVE:

Evaluate the diagnostic and prognostic value of LINC00086 and miR-214 in GC.

METHODS:

In this study, we determined the expression of LINC00086 and miR-214 in GC by qRT-PCR. Additionally, we investigated the relationship between various clinicopathological features of GC patients and LINC00086 or miR-214 expression, and evaluated the diagnostic and prognostic value of LINC00086 and miR-214 in GC.

RESULTS:

In this study, we found that plasma LINC00086 expression was significantly lower, whereas plasma miR-214 expression was significantly higher in GC patients than in normal individuals. LINC00086 and miR-214 exhibited high sensitivity and specificity in diagnosing GC. Additionally, GC patients with low LINC00086 or high miR-214 expression were likely to have larger tumors, lymphatic metastasis, larger TNM stage, and higher CEA and CA19-9 levels. Moreover, GC patients with low LINC00086 or high miR-214 expression showed lower survival rates. Lymphatic metastasis, LINC00086, and miR-214 are independent factors affecting patient diagnosis.

CONCLUSIONS:

LINC00086 and miR-214 are potentially diagnostic and prognostic markers for GC.

Keywords

Gastric cancer LINC00086 miR-214 diagnosis prognosis

1. Introduction

Gastric cancer (GC) is one of the most common and malignant cancers in the world today. An estimated 951,600 new stomach cancer cases and 723,100 deaths occurred in 2012 worldwide [1]. Generally, the morbidity and mortality of GC is higher in Eastern Asia than in most countries of the world, particularly in Korea, Mongolia, Japan, and China [1]. In China, more than 420,489 new cases and approximately 297,496 deaths were estimated as a result of GC in 2011 [2]. The early stage of GC, treated through complete surgical resection, has a good prognosis [3]. However, the 5-year survival rate of GC with metastases is approximately 30%, which is very poor [4]. Unfortunately, patients with GC show few symptoms during the early stages of the disease and diagnosis is usually difficult. Plasma carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4) are common markers which are useful in the diagnosis and prognosis of GC; however, the sensitivity and the specificity of CEA, CA19-9, and CA72-4 in GC still remains unsatisfactory [5]. The early diagnosis of GC is necessary for efficiently improving the outcome of GC patients. Therefore, identification of cancer biomarkers would be of great value.

Noncoding RNAs (ncRNAs) are transcripts that do not have the ability to code for proteins. They can be divided into several subtypes such as transfer RNA, small nucleolar RNA (snoRNA), ribosomal RNA (rRNA), microRNA (miRNA), and long non-coding RNA (lncRNA). ncRNA play critical regulative roles in proliferation, apoptosis, differentiation, metastasis, and development, possessing significant clinical value in GC [6]. Emerging evidence indicates that miRNAs [7, 8] and lncRNAs [9, 10, 11] can serve as diagnostic and prognostic markers in GC. Previous studies found that LINC00086 expression was downregulated in GC with lymphatic metastases when compared to GC patients with non-lymphatic metastases [10]. It was also reported that miR-214 could interact with LINC00086 [12]. However, the plasma LINC00086 and miR-214 expression and its potential diagnostic and prognostic value in GC is still unclear.

In this study, we collected the plasma of GC patients and normal individuals, measured the expression of LINC00086 and miR-214, and analyzed its clinical significance in GC. The aim of this study was to evaluate the diagnostic and prognostic value of LINC00086 and miR-214 in GC.

2. Methods

2.1 Patients and sample processing

Normal individuals (normal group; $n=$ 74) and patients with GC (GC group; $n=$ 168) were recruited between November 2013 and April 2017 from Dezhou Municipal Hospital for this study. All participants provided written informed consent. The study was conducted according to principles of the Helsinki Declaration of 1975 as revised in 1983, and was approved by the Ethics Committee of Dezhou Municipal Hospital. All patients had been diagnosed by imaging and post-surgery pathology. No treatment was applied before the sample collection. Post-operative follow-up was terminated on July 2017, with a range of 4–45 months (median months is month 22). Moreover, the normal individuals without benign gastric diseases and other cancers were gender- and age-matched with the GC groups. Procedures for sample collection and processing have been previously described [13]. Briefly, 5 mL of EDTA blood samples were collected from all participants, processed within 2 h of collection, and centrifuged for 10 min at 1,500 $\times\ g$ . The supernatant was isolated into RNase-free tubes and further centrifuged at 12,000 $\times\ g$ for 10 min at 4 ${}^{\circ}$ C to remove cells and debris. Plasma was stored at $-$ 80 ${}^{\circ}$ C until further processing.

2.2 RNA extraction and quantitative reverse transcription PCR (qRT-PCR)

Total RNA was extracted using TRIzol reagent (Invitrogen, Carlsbad, CA, USA), according to the manufacturer’s protocol. mRNA was reverse transcribed to cDNA using an miRcute miRNA first-strand cDNA synthesis kit (TIANGEN, Beijing, China) and a PrimeScript™RT reagent kit with gDNA Eraser (TIANGEN). LINC00086 expression was analyzed via qPCR using Power SYBR®Green PCR master mix (Applied Biosystems, Foster City, CA, USA); GAPDH was used as an internal control. miR-214 expression was detected via qPCR using an miRcute miRNA qPCR detection kit (TIANGEN); RNU6B served as the internal reference. qPCR was performed on a 7500 real-time PCR system (Applied Biosystems) using the following conditions: 95 ${}^{\circ}$ C for 5 min, followed by 40 cycles of 95 ${}^{\circ}$ C for 15 s and finally, 60 ${}^{\circ}$ C for 60 s. Primer sequences used for RT-qPCR are presented as follows: mir-214-F: 5 ${}^{\prime}$ -GCTGG ACAGAGTTGTCATGTG-3 ${}^{\prime}$ and R: 5 ${}^{\prime}$ -TGCTGTACA GGTGAGCGGAT-3 ${}^{\prime}$ ; U6-F: 5 ${}^{\prime}$ -CGCTTCGGCAGCA CATATACTAA-3 ${}^{\prime}$ and R: 5 ${}^{\prime}$ -TATGGAACGCTTCACG AATTTGC-3 $\prime$ ; LINC00086-F: 5 ${}^{\prime}$ -AGTCTGTTTTCTA GGCGGTGG-3 ${}^{\prime}$ and R: 5 ${}^{\prime}$ -CAGAGGCTTCTCCCTG CCAAC-3 ${}^{\prime}$ ; GAPDH-F: 5 ${}^{\prime}$ -CCCATCACCATCTTCC AGGAG-3 ${}^{\prime}$ and R: 5 ${}^{\prime}$ -GTTGTCATGGATGACCTTG GC-3 ${}^{\prime}$ . Gene expression was measured in triplicate, quantified using the 2 ${}^{-\Delta\Delta\text{CT}}$ method, and normalized to an internal control.

Figure 1.

The expression of LINC00086 (A) and miR-214 (B) in the plasma of normal individuals (Normal) and GC patients (GC) was measured via qRT-PCR, and the correlation between LINC00086 expression and miR-214 expression protein was showed (C).

2.3 Measurement of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) concentrations

The concentrations of CEA and CA19-9 in the serum of GC patients were measured via electrochemiluminescence immunoassay using the Elecsys 2010 analyzer (Roche, Basel, Switzerland) with matched reagents. In this study, the normal reference values were $<$ 3.4 ng/ml and $<$ 37.0 U/ml for the CEA and CA19-9 of healthy individuals, respectively. CEA and CA19-9 level was measured in triplicate.

2.4 Statistical analysis

SPSS 19.0 software (IBM, Armonk, NY, USA) was used to perform all statistical analyses. Data that did not conform to a normal distribution were described using the median and the 25th and 75th percentiles, while data that conformed to a normal distribution were described using the mean $\pm$ SD. The relationship between LINC00086 and miR-214 expression was analyzed by Spearman’s correlation. The Mann-Whitney U test was also applied as a non-parametric significance test between the two groups. The diagnostic value was analyzed by the receiver operating characteristic (ROC) curve, area under the curve (AUC), Youden index, sensitivity, and specificity to calculate the best cut-off value. Survival rate was calculated according to the Kaplan-Meier analysis and their effects on patient prognosis were analyzed by Cox-regression analysis. In all analyses, $p$ values are derived from two-tailed tests, and a $p<$ 0.05 was considered statistically significant.

Figure 2.

The diagnostic values of LINC00086 (A) and miR-214 (B) in GC were determined by receiver operating characteristic curve analysis.

Figure 3.

Kaplan-Meier survival curves for GC patients exhibiting LINC00086 expression (A), miR-214 expression (B), and a combination of LINC00086 and miR-214 expression (C).

3. Results

3.1 The expression of LINC00086 and miR-214 in GC patients

The expression of LINC00086 and miR-214 in plasma was measured via qRT-PCR. The results indicated that LINC00086 expression in normal individuals and GC patients was 0.585 (0.37–1.145) and 0.215 (0.160–0.330), respectively (Fig. 1A). miR-214 expression in normal individuals and GC patients were observed to be 1.705 (0.875–2.69) and 5.335 (3.718–6.770), respectively (Fig. 1B). Conclusively, the results demonstrated that LINC00086 expression was significantly lower in GC patients than normal individuals, while miR-214 expression was significantly higher ( $p<$ 0.001). There was a significant negative correlation between LINC00086 expression and miR-214 expression ( $r=$ $-$ 0.536, $p<$ 0.001, Fig. 1C).

3.2 Diagnostic value of LINC00086 and miR-214 in GC

We analyzed the performance of LINC00086 and miR-214 in diagnosing GC using ROC analysis. For the diagnostic value of LINC00086 in GC, at the optimal expression cut-off value of 0.300 (LINC00086 expression $<$ 0.300), the sensitivity was 72.6% (122/168) and specificity was 83.8% (62/74), with an AUC of 0.860 (Fig. 2A). For the diagnostic value of miR-214 in GC, at the optimal expression cut-off value of 3.975 (miR-214 expression $>$ 3.975), the sensitivity was 73.2% (123/168) and specificity was 91.9% (68/74), with an AUC of 0.880 (Fig. 2B).

3.3 Association of LINC00086 and miR-214 expression with the clinicopathological features of GC patients

The relationship between the expression of LINC00086 and miR-214 and the clinicopathological features of GC is shown in Table 1. Although there was no correlation between LINC00086 expression and age, sex, tumor location, or differentiation ( $p>$ 0.05), it exhibited significant correlation with tumor size, lymphatic metastasis, TNM stage, and the level of CEA and CA19-9 ( $p<$ 0.05). As expected, miR-214 expression was also significantly correlated with tumor size, lymphatic metastasis, TNM stage, and the level of CEA and CA19-9 ( $p<$ 0.05), but had not significantly with age, sex, tumor location, and differentiation ( $p>$ 0.05).

Table 1
Relationship between LINC00086 and miR-214 expression and clinicopathological features of GC patients

Characteristics	$n=$ 168	LINC00086 expression		miR-214 expression
		Median (25–75%)	$p$	Median (25–75%)	$p$
Age			0.875		0.934
$\geqslant$ 60	81	0.18 (0.14–0.27)		5.39 (3.67–6.92)
$<$ 60	87	0.22 (0.17–0.34)		5.28 (3.77–6.70)
Gender			0.610		0.791
Male	101	0.21 (0.16–0.32)		5.43 (3.82–6.73)
Female	67	0.22 (0.17–0.38)		5.28 (3.67–6.85)
Tumor location			0.521		0.895
Sinuses ventriculi	52	0.23 (0.16–0.34)		5.24 (3.95–6.70)
Cardia	36	0.21 (0.15–0.29)		5.28 (3.50–6.76)
Corpora ventriculi	47	0.21 (0.15–0.28)		5.53 (3.71–6.94)
Others	33	0.24 (0.18–0.43)		5.61 (3.40–7.07)
Tumor size			0.038		0.017
$\geqslant$ 5 cm	78	0.26 (0.17–0.36)		4.71 (3.09–5.94)
$<$ 5 cm	90	0.20 (0.15–0.30)		5.71 (4.37–7.28)
Differentiation			0.282		0.473
Well $+$ moderate	55	0.23 (0.17–0.33)		5.11 (3.65–6.67)
Poor	113	0.21 (0.15–0.33)		5.39 (3.77–6.87)
Lymphatic metastasis			0.038		$<$ 0.001
No	53	0.24 (0.18–0.38)		4.05 (2.65–5.67)
Yes	115	0.20 (0.15–0.29)		5.73 (4.59–7.22)
TNM stage			0.018		$<$ 0.001
I $+$ II	63	0.25 (0.18–0.37)		4.41 (2.72–5.86)
III $+$ IV	105	0.20 (0.15–0.29)		5.73 (4.56–7.22)
CEA			0.003		$<$ 0.001
Normal	83	0.24 (0.18–0.36)		4.43 (2.72–5.66)
High	85	0.19 (0.14–0.29)		6.40 (4.83–7.52)
CA19-9			$<$ 0.001		$<$ 0.001
Normal	90	0.24 (0.18–0.34)		4.45 (2.96–5.73)
High	78	0.19 (0.14–0.29)		6.48 (4.94–7.57)

Table 2

Different prognostic parameters of GC patients were evaluated by Cox-regression univariate and multivariate analysis

Parameters	Univariate analysis		Multivariate analysis
	Risk ratio (95% CI)	$p$	Risk ratio (95%CI)	$p$
Age	0.760 (0.428–1.348)	0.347
Gender	1.756 (0.942–3.274)	0.077
Tumor location	1.064 (0.814–1.390)	0.650
Tumor size	1.135 (1.048–1.375)	0.017	1.268 (0.708–2.272)	0.424
Differentiation	0.880 (0.477–1.623)	0.682
Lymphatic metastasis	2.666 (1.794–3.961)	$<$ 0.001	2.375 (1.242–3.674)	0.017
TNM stage	1.892 (1.313–2.726)	0.011	1.516 (0.595–3.861)	0.383
CEA	2.064 (1.440–2.958)	0.008
CA19-9	2.633 (1.800–3.852)	$<$ 0.001	1.237 (0.931–1.787)	0.162
LINC00086 expression	0.035 (0.007–0.055)	$<$ 0.001	0.335 (0.060–0.758)	0.007
miR-214 expression	4.226 (3.068–6.408)	$<$ 0.001	3.764 (1.139–6.218)	0.003

CI: confidence interval.

3.4 Prognostic value of LINC00086 and miR-214 for GC

During the follow-up period (a time period of 4–45 months; median time is month 22), 48 GC patients died. GC patients were divided into two groups according to the median of LINC00086 expression (which was 0.21): the low LINC00086 group ( $<$ 0.21) and the high LINC00086 group ( $\geqslant$ 0.21). During follow-up, the mortality of the GC patients in the low and high LINC00086 groups was observed to be 42.86% (36/84) and 14.28% (12/84), respectively. GC patients had a significantly lower survival rate in the low LINC00086 group than the high LINC00086 group (log rank $\chi^{2}$ $=$ 15.276; $p<$ 0.001; Fig. 3A). GC patients were also divided into two groups according to the median of miR-214 expression (which was 5.29): the low miR-214 group ( $<$ 5.29) and high miR-214 group ( $\geqslant$ 5.29). During follow-up, the mortality of the GC patients in the low and high miR-214 groups was observed to be 13.10% (11/84) and 44.05% (37/84), respectively. GC patients had a significantly lower survival rate in the high miR-214 group than the low miR-214 group (log rank $\chi^{2}$ $=$ 13.195; $p<$ 0.001; Fig. 3B). Furthermore, GC patients were divided into four groups according to the median of the LINC00086 expression (which was 0.21) and miR-214 expression (which was 5.29): low LINC00086 $+$ low miR-214, low LINC00086 $+$ high miR-214, high LINC00086 $+$ low miR-214, and high LINC00086 $+$ high miR-214. The mortality of GC patients in the four groups were 17.39% (4/23), 52.46% (32/61), 11.48% (7/61), and 21.74% (5/23), respectively. GC patients were observed to have significantly low survival rates in the low LINC00086 $+$ high miR-214 group than the other three groups (log rank $\chi^{2}$ $=$ 18.461; $p<$ 0.001; Fig. 3C). Additionally, Cox-regression univariate and multivariate analyses were used to evaluate whether LINC00086 and miR-214 expression and various clinicopathological parameters were independent prognostic parameters of patient outcomes. The results, shown in Table 2, suggest that LINC00086 and miR-214 expression and lymphatic metastasis are independent prognostic parameters for the overall survival of GC patients.

4. Discussion

In this study we found that the LINC00086 expression was significantly lower in GC patients than in normal individuals, while miR-214 expression was significantly higher. Additionally, the main findings of this study suggested that LINC00086 and miR-214 are potentially diagnostic and prognostic markers for GC. Combined, LINC00086 and miR-214 contributed in improving the predicted efficiency of prognosis in GC patients.

Plasma CEA, CA19-9, and CA72-4 are common markers which can help in the follow-up (if initially elevated) and in diagnosis tumor recurrence. However, the sensitivity and the specificity of CEA, CA19-9, and CA72-4 in GC remain unsatisfactory. Liang et al. found that the diagnosed sensitivity of CEA, CA19-9, and CA72-4 varied between 20.1–27.6% individually, and increased to 48.2% when they were considered in combination while diagnosing GC [14]. Increasing evidences have verified that lncRNAs are involved in many biological functions and play crucial roles in GC tumorigenesis and progression [15, 16]. Dysregulated lncRNAs could serve as novel biomarkers for the early diagnosis and prognosis of GC [9, 11]. LINC00086, significantly associated with overall survival, is also observed to be significantly downregulated in GC patients with lymphatic metastases when compared to GC patients with non-lymphatic metastases [10]. In the present study, we found that LINC00086 expression was significantly lower in the plasma of GC patients than in the plasma of normal individuals. ROC curve analysis found that LINC00086 exhibited high sensitivity and specificity in diagnosing GC (sensitivity: 72.6%; specificity: 83.8%; area under the curve: 0.860), which was more than the sensitivity and specificity exhibited by plasma CEA, CA19-9, and CA72-4 [14]. Additionally, GC patients with low LINC00086 expression were likely to have larger tumors, lymphatic metastasis, larger TNM stage, and higher CEA and CA19-9 levels. However, LINC00086 expression had no significant correlation with age, sex, tumor location, and differentiation. Moreover, GC patients with low LINC00086 expression were also shown to exhibit lower survival rates via the Kaplan-Meier survival curve analysis.

Accumulating evidence suggests that lncRNAs act as microRNA sponges by binding to miRNAs and regulating the biological processes of cancer. A previous study found that LINC00086 targeted miR-214 in nasopharyngeal carcinoma [12]. The findings of the present study found that LINC00086 expression exhibited a significantly negative correlation with miR-214 expression. Another previous study also found that plasma miR-214 was significantly higher in patients with GC than in controls; high plasma miR-214 significantly correlated with distant metastasis, where the AUC value of miR-214 was 0.845 by ROC analysis [17]. miR-214 regulated GC cell proliferation, migration, and invasion by targeting PTEN [18]. Similar to our results, these studies also suggested that miR-214 expression was upregulated in the plasma of GC patients, which correlated with GC cell proliferation, migration, and invasion. Our results showed that miR-214 expression was significantly lower in the plasma of GC patients than in the plasma of normal individuals. ROC curve analysis found that miR-214 exhibited high sensitivity and specificity in diagnosing GC (sensitivity: 73.2%; specificity: 91.9%; area under the curve: 0.880) [14]. GC patients with high miR-214 expression were likely to have larger tumors, lymphatic metastasis, larger TNM stage, and higher CEA and CA19-9 levels. However, miR-214 expression had no significant correlation with age, sex, tumor location, and differentiation. Moreover, GC patients exhibiting high miR-214 expression had lower survival rates, as shown by the Kaplan-Meier survival curve analysis. Finally, GC patients with low LINC00086 and high miR-214 expression had significantly lower survival rates than the other three groups of GC patients (low LINC00086 and low miR-214 expression, high LINC00086 and low miR-214 expression, and high LINC00086 and high miR-214 expression).

Previous study found miR-214 expression is down-regulated in Ulcerative Colitis, upregulation miR-214 could decrease the level of INF- $\gamma$ [19]. Whereas, Zhao et al. found that miR-214 promoted the release of inflammatory cytokines TNF- $\alpha$ and IL-6 in murine macrophages [20]. These results had shown that miR-214 plays a different role in different diseases. Additionally, these studies suggest that miR-214 expression was elevated by cancer or other factors. However, in this study we did not rule out the effects of other diseases include benign gastric diseases on LINC00086 and miR-214 expression. In future research, we will further expand the sample collection of healthy and gastric cancer populations and strengthen the control of potential confounding factors to further study the role of protein in the diagnosis and prognosis of gastric cancer.

In conclusions, LINC00086 expression was significantly lower and miR-214 expression was significantly higher in GC patients than in normal individuals. LINC00086 and miR-214 are potential diagnostic and prognostic markers for GC. The exact mechanism that determines the impacts of LINC00086 expression on GC tumorigenesis and metastasis, and also the regulation of miR-214 expression will be investigated in our future research.

Footnotes

Conflict of interest

None.

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Potential diagnostic and prognostic value of plasma long noncoding RNA LINC00086 and miR-214 expression in gastric cancer

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Methods

2.1 Patients and sample processing

2.2 RNA extraction and quantitative reverse transcription PCR (qRT-PCR)

2.4 Statistical analysis

3.1 The expression of LINC00086 and miR-214 in GC patients

3.2 Diagnostic value of LINC00086 and miR-214 in GC

3.3 Association of LINC00086 and miR-214 expression with the clinicopathological features of GC patients

Table 1 Relationship between LINC00086 and miR-214 expression and clinicopathological features of GC patients

4. Discussion

Footnotes

Conflict of interest

References

Table 1
Relationship between LINC00086 and miR-214 expression and clinicopathological features of GC patients