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Abstract

BACKGROUND:

microRNA (miR)-1290 was previously indicated to promote esophageal squamous cell carcinoma (ESCC) progression via regulating its target gene nuclear factor I/X (NFIX).

OBJECTIVE:

To investigate clinical significance of miR-1290 and NFIX in ESCC.

METHODS:

Quantitative real-time PCR was performed to detect miR-1290 and NFIX mRNA expression in ESCC tissues. Associations of miR-1290 and/or NFIX mRNA expression with various clinicopathological features and prognosis in ESCC patients were statistically evaluated.

RESULTS:

Compared to noncancerous esophageal mucosa, miR-1290 expression was upregulated, while NFIX mRNA expression was downregulated in ESCC tissues. There was a significantly negative correlation between miR-1290 and NFIX expression in ESCC tissues ( $r=-$ 0.427, $P=$ 0.01). Interestingly, miR-1290-high and/or NFIX-low expression were all significantly associated with positive lymph node metastasis and advanced tumor-node-metastasis stage of ESCC patients (all $P<$ 0.05). Moreover, miR-1290 upregulation and NFIX downregulation both correlated short overall and disease-free survivals of ESCC patients. Importantly, the prognostic value of combined miR-1290 and NFIX expression was more significant than those considered alone.

CONCLUSIONS:

Our data suggest that the dysregulation of miR-1290-NFIX axis may play crucial roles in esophageal carcinogenesis and progression. We also confirmed miR-1290 and its target gene NFIX as independent prognostic factors for ESCC patients.

Keywords

Esophageal squamous cell carcinoma microRNA-1290 nuclear factor i/X prognosis clinicopathological characteristics

1. Introduction

Esophageal cancer, one of the most aggressive human cancers, represents the sixth leading cause of cancer-related mortality worldwide and the fourth main cause of cancer-related death in China [1]. With an increasing incidence, more than 48,000 Chinese people were suffering from esophageal cancer [2]. Among them, over 95% is esophageal squamous cell carcinoma (ESCC), which has more malignant phenotypes than esophageal adenocarcinoma [3]. Although there have been many advanced techniques developed for the diagnosis and treatment of ESCC, the patients’ prognosis is failed to be improved. The five-year overall survival rate of ESCC patients after esophagectomy remains approximately 20% [4]. Growing clinical evidence shows that the late appearance of symptoms, rapid progression, local recurrence, and metastasis mainly result in the unfavorable prognosis [5]. Since the molecular mechanisms underlying the carcinogenesis and progression of ESCC are still unclear, it is extremely necessary to identify novel and sufficient biomarkers with high specificity and sensitivity for the early diagnosis and prognosis of ESCC patients.

microRNAs (miRNAs), a group of small, single stranded non-coding RNAs with 18–25 nucleotides in length, can negatively regulate gene expression by binding to 3’-untranslated region of the corresponding target mRNAs at a post-transcriptional level [6]. Since miRNAs have been indicated to be involved into many biological processes, such as cell development, differentiation, proliferation, cell cycle and apoptosis, more and more attentions on roles of miRNAs in human cancers have been paid [7]. Accumulating studies have reported that miRNAs may function as either oncomiRNAs or tumor suppressive miRNAs with a cancer-dependent manner [8]. Especially, several miRNAs have been identified as biomarkers for cancer diagnosis and prognosis. For example, Komatsu et al. [9] indicated that high level of plasma miR-23a, which tended to correlate with lymphatic invasion and deep depth of invasion, was an independent risk factor for chemoresistance in ESCC; Jin et al. [10] found that ectopic miR-630 expression inhibited proliferation, invasion and metastasis, whereas miR-630 knockdown induced proliferation, invasion, metastasis and epithelial-mesenchymal transition traits of ESCC cells; Komatsu et al. [11] explored that the overexpression of miR-21 contributed to chemoresistance and circulating miR-21 in plasma of patients with ESCC could be a useful biomarker for predicting chemoresistance. These evidence supports a role for miRNAs in multiple cancer development and progression, including ESCC.

miR-1290, localized in 1p36.13, was originally discovered in human embryonic stem cells [12]. Growing evidence indicates that miR-1290 may play a role in several human cancers, including laryngeal carcinoma, ESCC, breast cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, colon cancer and castration-resistant prostate cancer [13, 14, 15, 16, 17, 18, 19, 20]. Especially, Li et al. [14] found that miR-1290 promoted cell proliferation and metastasis of ESCC cells; Subsequently, Mao et al. [21] identified nuclear factor I/X (NFIX) as a direct target gene of miR-1290 and confirmed that miR-1290 may function as an oncomiRNA in the progression of ESCC via regulating NFIX. However, the clinical significance of miR-1290 and NFIX in esophageal carcinogenesis has not been fully elucidated. To address this problem, the current study performed quantitative real-time PCR to detect miR-1290 and NFIX mRNA expression in ESCC tissues. Then, associations of miR-1290 and/or NFIX mRNA expression with various clinicopathological features and prognosis in ESCC patients were statistically evaluated.

2. Materials and methods

2.1 Ethic statement

The current study was approved by the Ethic Committee of Huai’an First People’s Hospital. Prior informed consent was signed by all the patients enrolled in this study according to the guidelines of Huai’an First People’s Hospital. All tissue specimens were handled and made anonymous based on the ethical and legal standards.

Table 1
Associations of miR-1290 and/or NFIX mRNA expression with various clinicopathological characteristics of 100 ESCC patients

Clinical variables	No. of patients	miR-1290-high	$P$	NFIX-low	$P$	miR-1290-high/	$P$
	(%)	(n, %)		(n, %)		NFIX-low (n, %)
Age (year)
$\leqslant$ 60	40 (40.00)	22 (55.00)	NS	22 (55.00)	NS	12 (30.00)	NS
$>$ 60	60 (60.00)	29 (48.33)		30 (50.00)		20 (33.33)
Gender
Male	68 (68.00)	35 (51.47)	NS	36 (52.94)	NS	22 (32.35)	NS
Female	32 (32.00)	16 (50.00)		16 (50.00)		10 (31.25)
Tumor location
Upper1/3-middle1/3	78 (78.00)	40 (51.28)	NS	40 (51.28)	NS	26 (33.33)	NS
Lower1/3	22 (22.00)	11 (50.00)		12 (54.55)		6 (27.27)
Lymph node metastasis
Negative	34 (34.00)	5 (14.71)	0.002	5 (14.71)	0.006	0 (0)	$<$ 0.001
Positive	66 (66.00)	46 (69.70)		47 (71.21)		32 (48.48)
TNM stage
Absent	30 (30.00)	2 (6.67)	$<$ 0.001	3 (10.00)	$<$ 0.001	0 (0)	$<$ 0.001
Present	70 (70.00)	49 (70.00)		49 (70.00)		32 (45.71)
Histological differentiation
Well	28 (28.00)	15 (53.57)	NS	15 (53.57)	NS	8 (28.57)	NS
Moderate $\sim$ poor	72 (72.00)	36 (50.00)		37 (51.39)		24 (33.33)

‘NS’ refers to difference without statistical significance.

2.2 Patients and tissue samples

One hundred pairs of primary ESCC and matched non-cancerous esophageal mucosa (more than 5 cm away from the tumor margin) tissue specimens were collected from 100 patients who underwent esophagectomy in the Department of Gastroenterology, Huai’an First People’s Hospital between Janurary 2010 and December 2012. The diagnosis was confirmed according to clinical examination and histopathological analysis of the tissue specimens which performed by two pathologists. None of the patients received radiotherapy or chemotherapy before surgery. Tumor-Node-Metastasis (TNM) stage was classified according to the 7 ${}^{\rm th}$ edition of TNM classification of Union Internationale Contra Cancrum [22]. Table 1 summarized ESCC patients’ clinicopathological characteristics, including age, gender, tumor location, lymph node metastasis, TNM stage and pathological grade. All the samples were collected and immediately snap frozen in liquid nitrogen and stored at $-$ 80 ${{}^{\circ}}$ C untill further use.

For the survival analysis, all 100 ESCC patients received follow-up every three months during the first postoperative year and for a minimum of six months afterwards for survival and recurrence inquiry until death or until the end of the investigation. The median follow-up period was 33 months (range 2–70 months). Mean and median times to overall survival were 40.6 and 32.3 months, respectively. Mean and median times to disease-free survival were 36.9 and 30.0 months, respectively.

2.3 RNA extraction and real-time quantitative RT-PCR

Expression levels of miR-1290 and NFIX mRNA in 100 pairs of primary ESCC and matched non-cancerous esophageal mucosa was detected by real-time quantitative RT-PCR according to the protocol described in our previous study [23]. The sequence-specific primer pairs were used for quantitative PCR were listed as following: miR-1290, (forward) 5’-AGC GTG TGT CGT GGA GTC-3’, (reverse) 5’-TCG TGA GAT GAA GCA CTG TAG-3’; U6, (forward) 5’-CTC GCT TCG GCA GCA CA-3’, (reverse) 5’-AAC GCT TCA CGA ATT TGC GT-3’; NFIX, (forward) 5’-TGT TCC CGA CCG TTA CTT TG-3’, (reverse) 5’-TGT ATT TCC CGC TAT CTT CCT G-3’; GAPDH, (forward) 5’-GCT GAG TAT GTC GTG GAG TC-3’, (reverse) 5’-AGT TGG TGG TGC AGG ATG C-3’. Relative expression levels of miRNA and mRNA were calculated with the 2 ${}^{\rm-\Delta\Delta Ct}$ method. Each sample was examined in triplicate.

2.4 Statistical analysis

Data were shown as mean $\pm$ standard deviation (SD). The differences of miR-1290/NFIX mRNA expression between ESCC and non-cancerous groups were analyzed using Student’s $t$ test. The correlation between miR-1290 expression and NFIX mRNA expression in ESCC tissues was determined by Spearman Correlation analysis. Associations between miR-1290/NFIX mRNA expression and various clinicopathological characteristics were evaluated using Fisher’s exact probability test. Survival curves were calculated using the Kaplan-Meier method, and differences were analyzed with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. Statistical significance was determined as $P$ value $<$ 0.05.

Table 2
Univariate analysis of overall and disease-free survivals in 100 patients with ESCC

Features	Overall survival		Disease-free survival
	Hazard ratio (HR) (95% confidence intervals, CI)	$P$	HR (95% CI)	$P$
Age (year)
$\leqslant$ 60 vs. $>$ 60	0.90 (0.58 $\sim$ 1.35)	NS	0.82 (0.24–1.26)	NS
Gender
Male vs. female	0.68 (0.13 $\sim$ 1.22)	NS	0.57 (0.23 $\sim$ 1.12)	NS
Tumor location
Upper1/3-middle1/3 vs. lower1/3	0.92 (0.39 $\sim$ 1.85)	NS	0.88 (0.37 $\sim$ 1.61)	NS
Lymph node metastasis
Negative vs. positive	3.72 (1.96 $\sim$ 7.57)	0.001	3.59 (1.29 $\sim$ 7.01)	0.001
TNM stage
Absent vs. present	4.22 (1.79 $\sim$ 9.03)	$<$ 0.001	3.98 (1.58 $\sim$ 8.67)	$<$ 0.001
Histological differentiation
Well vs. moderate $\sim$ poor	1.93 (0.68 $\sim$ 4.02)	0.03	1.65 (0.56 $\sim$ 3.88)	0.03
miR-1290 expression
Low vs. high	2.60 (1.01 $\sim$ 4.88)	0.01	2.36 (1.00 $\sim$ 4.13)	0.01
NFIX expression
High vs. low	2.69 (1.03 $\sim$ 4.96)	0.01	2.38 (1.01 $\sim$ 4.27)	0.01
miR-1290/NFIX expression
Other three groups vs. high/low	3.05 (1.19 $\sim$ 6.12)	0.006	2.97 (1.10 $\sim$ 6.06)	0.006

‘NS’ refers to difference without statistical significance.

Figure 1.

MiR-1290 and NFIX mRNA expression in ESCC tissues. (A) Relative expression of miR-1290 in ESCC tissues and adjacent non-cancerous esophageal mucosa; (B) Relative expression of NFIX mRNA in ESCC tissues and adjacent non-cancerous esophageal mucosa; (C) Spearman correlation analysis of miR-1290 and NFIX mRNA expression in ESCC tissues.

3. Results

3.1 MiR-1290 upregulation and NFIX downregulation in ESCC tissues

The expression levels of miR-1290 in ESCC tissues were significantly higher than those in adjacent non-cancerous esophageal mucosa (ESCC vs. non-cancerous tissues: 3.74 $\pm$ 2.32 vs. 1.59 $\pm$ 0.89, $P<$ 0.001, Fig. 1A), while NFIX mRNA expression was markedly decreased in ESCC tissues (ESCC vs. non-cancerous tissues: 1.43 $\pm$ 0.87 vs. 3.53 $\pm$ 1.92, $P<$ 0.001, Fig. 1B). In addition, the spearman correlation analysis demonstrated that there was a significantly negative correlation between miR-1290 and NFIX mRNA expression in ESCC tissues ( $r=-$ 0.427, $P=$ 0.01, Fig. 1C).

3.2 MiR-1290 upregulation and/or NFIX downregulation associate with aggressive progression of ESCC patients

Table 3
Multivariate analysis of overall and disease-free survivals in 100 patients with ESCC

Features	Overall survival		Disease-free survival
	HR (95% CI)	$P$	HR (95% CI)	$P$
Lymph node metastasis	2.41 (0.99 $\sim$ 4.28)	0.01	2.17 (0.87 $\sim$ 4.02)	0.01
TNM stage	3.18 (1.09 $\sim$ 6.42)	0.008	3.07 (1.03 $\sim$ 6.38)	0.008
Histological differentiation	1.05 (0.21 $\sim$ 2.37)	NS	1.00 (0.13 $\sim$ 2.03)	NS
miR-1290 expression	1.97 (1.00 $\sim$ 4.19)	0.03	1.81 (1.00 $\sim$ 4.06)	0.03
NFIX expression	2.18 (1.06 $\sim$ 4.76)	0.03	2.11 (1.03 $\sim$ 4.32)	0.03
miR-1290/NFIX expression	2.82 (1.23 $\sim$ 5.95)	0.01	2.57 (1.19 $\sim$ 5.53)	0.01

‘NS’ refers to difference without statistical significance.

Figure 2.

Kaplan-Meier survival analysis for overall and diseasefree survivals of ESCC patients based on miR-1290 expression (A and B, respectively), NFIX expression (C and D, respectively), and miR-1290/NFIX expression (E and F, respectively).

All 100 ESCC patients were divided into miR-1290-low/high ( $n=$ 49/51) and NFIX-low/high ( $n=$ 52/48) groups using the median values of miR-1290 (3.56) and NFIX mRNA (1.33) expression levels in ESCC tissues as cutoff points, respectively. As shown in Table 1, miR-1290 upregulation was significantly associated with positive lymph node metastasis ( $P=$ 0.002) and advanced TNM stage ( $P<$ 0.001); In contrast, ESCC patients with low NFIX expression more frequently occurred lymph node metastasis ( $P=$ 0.006) and had high TNM stage ( $P<$ 0.001). However, there were no significant associations of miR-1290 expression with patients’ age and gender, tumor location and histological differentiation (all $P>$ 0.05, Table 1).

Among 100 ESCC patients, 20 (20.00%), 32 (32.00%), 29 (29.00%) and 19 (19.00%) were respectively belonged to miR-1290-low/NFIX-low, miR-1290-high/NFIX-low, miR-1290-low/NFIX-high, miR -1290-high/NFIX-high groups. Notably, the associations of combined miR-1290/NFIX expression with lymph node metastasis ( $P<$ 0.001, Table 1) and TNM stage ( $P<$ 0.001, Table 1) were more significant than miR-1290 or NFIX individually.

3.3 MiR-1290 upregulation and/or NFIX downregulation predict poor prognosis in ESCC patients

Kaplan-Meier survival analysis demonstrated that high miR-1290 expression was significantly associated with shorter overall ( $P=$ 0.005, Fig. 2A) and disease-free ( $P=$ 0.002, Fig. 2B) survivals of ESCC patients; In contrast, the patients with low NFIX expression more often had short overall and disease-free survivals than those with high NFIX expression (both $P=$ 0.003, Fig. 2C and D, respectively); Interestingly, ESCC patients with the combined miR-1290- high/NFIX-low expression had the shortest overall and disease-free survivals compared to patients with miR-1290-high/NFIX-high, miR-1290-low/NFIX-low and miR-1290-low/NFIX-high expression (both $P<$ 0.001, Fig. 2E and F, respectively).

Univariate analysis indicated that lymph node metastasis (both $P=$ 0.001, Table 2), TNM stage (both $P<$ 0.001, Table 2), histological differentiation (both $P=$ 0.03, Table 2), miR-1290 expression (both $P=$ 0.01, Table 2), NFIX expression (both $P=$ 0.01, Table 2) and miR-1290/NFIX expression (both $P=$ 0.006, Table 2) were all significantly associated with overall and disease-free survivals of ESCC patients. Moreover, multivariate analysis showed that lymph node metastasis (both $P=$ 0.01, Table 3), TNM stage (both $P=$ 0.008, Table 3), miR-1290 expression (both $P=$ 0.03, Table 3), NFIX expression (both $P=$ 0.03, Table 3) and miR-1290/NFIX expression (both $P=$ 0.01, Table 3) were independent prognostic factors for ESCC.

4. Discussion

As one of the extremely aggressive human cancer, ESCC often leads to a dismal prognosis [5]. The identification of novel diagnostic and prognostic biomarkers for ESCC is urgently needed to improve clinical outcome of patients and to develop effective therapeutic strategies of this malignancy. In the current study, we found that miR-1290 and NFIX mRNA expression in ESCC were respectively higher and lower than those in matched noncancerous esophageal mucosa. According to multi-clinical classifications, miR-1290 and/or NFIX mRNA level varied markedly with lymph node metastasis and TNM stage. Univariate analysis showed that lymph node metastasis, TNM stage, histological differentiation, miR-1290 expression, NFIX expression and miR-1290/NFIX combined expression were prognostic factors for survival. Multivariate analysis showed that lymph node metastasis, TNM stage, miR-1290 expression, NFIX expression and miR-1290/NFIX combined expression were independent prognostic factors for ESCC. These findings indicated for the first time that a combined analysis of miR-1290 expressions as well as its target gene NFIX expression may help predict the prognosis in ESCC patients.

Accumulating studies have demonstrated that miR-1290 may function as an oncogenic miRNA in various human cancers. Mo et al. [16] observed that miR-1290 was overexpressed in NSCLC, and serum miR-1290 might be used as a potential prognostic biomarker for non-small cell lung cancer; Wu et al. [19] found that miR-1290 was dramatically up-regulated in clinical colon cancer tissues and its upregulation postponed cytokinesis leading to the formation of multinucleated cells; Janiszewska et al. [13] identified miR-1290 as the new oncomiR involved in laryngeal squamous cell carcinoma pathogenesis and demonstrated that the oncogenic potential of miR-1290 might be expressed by the involvement in downregulation of its target genes MAF and ITPR2; Lin et al. [17] revealed that miR-1290 was highly expressed in SGC-7901 gastric cancer cells as well as in clinical gastric cancer samples, which was correlated with clinical stages, depth of invasion and lymph nodemetastasis; Imaoka et al. [24] integrated the comprehensive miRNA array analysis and qPCR validation to identify circulating miR-1290 as a novel diagnostic and prognostic biomarker in human colorectal cancer; Huang et al. [20] confirmed plasma exosomal miR-1290 and miR-375 as promising prognostic biomarkers for castration-resistant prostate cancer patients; Li et al. [18] performed miRNA array analysis to identify elevated serum miR-1290 may accurately distinguish patients with low-stage pancreatic cancer from healthy and disease controls. miRNAs exert their functions via regulating the corresponding target genes. NFIX, a member of the nuclear factor one (NFI) protein family, has been confirmed as one of the direct target genes of miR-1290 [21]. NFIs act as transcriptional activators and/or repressors of cellular and viral genes. Especially in vertebrates, there are four NFI genes, NFIA, NFIB, NFIC, and NFIX, which encode for proteins with a conserved N-terminal DNA-binding and dimerization domain and a C-terminal transactivation/repression domain [25]. NFI genes has been demonstrated to expressed in various organs, including brain, lung, liver, intestine, muscle, connective tissue, skeletal elements and hematopoiesis, suggesting that these genes may exert different functions with a cell type-dependent manner [26]. Regarding to human cancers, Mao et al. [21] identified the specific targeting site of miR-1290 in the 3’-UTR of NFIX and confirmed the inverse correlation between the levels of miR-1290 and NFIX protein and mRNA in ESCC tissue samples; They also demonstrated that miR-1290 could promote proliferation, migration and invasion via the negative regulation of NFIX expression. In the current study, the negative correlation between miR-1290 and NFIX mRNA expression in ESCC tissues was confirmed based on a large clinical cohort. More interestingly, we found that the associations of combined miR-1290/NFIX expression with aggressive clinical progression and unfavorable prognosis in ESCC patients were more significant than those considered alone.

In conclusion, our data suggest that the dysregulation of miR-1290-NFIX axis may play crucial roles in esophageal carcinogenesis and progression. We also confirmed miR-1290 and its target gene NFIX as independent prognostic factors for ESCC patients. Additional investigation is required to fully elucidate the molecular mechanism underlying the involvement of miR-1290/NFIX axis in regulating the oncogenesis, progression and prognosis of ESCC.

Conflict of interest

None.

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Prognostic value of combined and individual expression of microRNA-1290 and its target gene nuclear factor I/X in human esophageal squamous cell carcinoma

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1. Introduction

2. Materials and methods

2.1 Ethic statement

Table 1 Associations of miR-1290 and/or NFIX mRNA expression with various clinicopathological characteristics of 100 ESCC patients

2.3 RNA extraction and real-time quantitative RT-PCR

2.4 Statistical analysis

Table 2 Univariate analysis of overall and disease-free survivals in 100 patients with ESCC

3.1 MiR-1290 upregulation and NFIX downregulation in ESCC tissues

3.2 MiR-1290 upregulation and/or NFIX downregulation associate with aggressive progression of ESCC patients

Table 3 Multivariate analysis of overall and disease-free survivals in 100 patients with ESCC

4. Discussion

Conflict of interest

References

Table 1
Associations of miR-1290 and/or NFIX mRNA expression with various clinicopathological characteristics of 100 ESCC patients

Table 2
Univariate analysis of overall and disease-free survivals in 100 patients with ESCC

Table 3
Multivariate analysis of overall and disease-free survivals in 100 patients with ESCC