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Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype.

ABSTRACT: To identify molecular biologic differences between two gastric adenocarcinoma subgroups presenting different prognoses through the analysis of microRNA and protein expression.Array technologies were used to generate 1146 microRNAs and 124 proteins expression profiles of samples from 60 patients with gastric cancer. For the integrative analysis, we used established mRNA expression data published in our previous study. Whole mRNA expression levels were acquired from microarray data for 60 identical gastric cancer patients. Two gastric adenocarcinoma subgroups with distinct mRNA expression profiles presented distinctly different prognoses. MicroRNA and protein expression patterns were compared between gastric cancer tissue and normal gastric tissue and between two different prognostic groups. Aberrantly expressed microRNA, associated mRNA, and protein in patients with poor-prognosis gastric cancer were validated by quantitative reverse transcription polymerase chain reaction and immunochemistry in independent patients.We obtained the expression data of 1146 microRNAs and 124 cancer-related proteins. Four microRNAs were aberrantly expressed in the two prognostic groups and in cancer vs non-cancer tissues (P < 0.05). In the poor-prognosis group, miR-196b, miR-135b, and miR-93 were up-regulated and miR-29c* was down-regulated. miR-196b expression positively correlated with Homeobox A10 (HOXA10) expression (r = 0.726, P < 0.001), which was significantly increased in poor-prognosis patients (P < 0.001). Comparing gastric cancer with non-cancer tissues, 46/124 proteins showed differential expression (P < 0.05); COX2 (P < 0.001) and cyclin B1 (P = 0.017) were clearly over-expressed in the poor-prognosis group.Co-activation of miR-196b and HOXA10 characterized a poor-prognosis subgroup of patients with gastric cancer. Elucidation of the biologic function of miR-196b and HOXA10 is warranted.

SUBMITTER: Lim JY

PROVIDER: S-EPMC3819543 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype.

Lim Jae Yun JY Yoon Sun Och SO Seol So-Young SY Hong Soon Won SW Kim Jong Won JW Choi Seung Ho SH Lee Ju-Seog JS Cho Jae Yong JY

World journal of gastroenterology 20131101 41

<h4>Aim</h4>To identify molecular biologic differences between two gastric adenocarcinoma subgroups presenting different prognoses through the analysis of microRNA and protein expression.<h4>Methods</h4>Array technologies were used to generate 1146 microRNAs and 124 proteins expression profiles of samples from 60 patients with gastric cancer. For the integrative analysis, we used established mRNA expression data published in our previous study. Whole mRNA expression levels were acquired from mic ...[more]

PMID: 24222951

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Project description:The cross-talk between epigenetics and miRNA expression plays an important role in human tumorigenesis. Herein, the regulation and role of miR-196b-5p in gastric cancer was investigated. qRT-PCR demonstrated that miR-196b-5p is significantly overexpressed in human gastric cancer tissues (P < 0.01). In addition, it was determined that HOXA10, a homeobox family member and host gene for miR-196b-5p, is overexpressed and positively correlated with miR-196b-5p expression levels (P < 0.001). Quantitative pyrosequencing methylation analysis demonstrated significantly lower levels of DNA methylation at the HOXA10 promoter in gastric cancer, as compared with nonneoplastic gastric mucosa specimens. 5-Aza-2'-deoxycytidine treatment confirmed that demethylation of HOXA10 promoter induces the expression of HOXA10 and miR-196b-5p in gastric cancer cell model systems. Using the Tff1 knockout mouse model of gastric neoplasia, hypomethylation and overexpression of HOXA10 and miR-196b-5p in gastric tumors was observed, as compared with normal gastric mucosa from Tff1 wild-type mice. Mechanistically, reconstitution of TFF1 in human gastric cancer cells led to an increased HOXA10 promoter methylation with reduced expression of HOXA10 and miR-196b-5p. Functionally, miR-196b-5p reconstitution promoted human gastric cancer cell proliferation and invasion in vitro In summary, the current data demonstrate overexpression of miR-196b-5p in gastric cancer and suggest that TFF1 plays an important role in suppressing the expression of miR-196b-5p by mediating DNA methylation of the HOXA10 promoter. Loss of TFF1 expression may promote proliferation and invasion of gastric cancer cells through induction of promoter hypomethylation and expression of the HOXA10/miR-196b-5p axis.Implications: This study indicates that loss of TFF1 promotes the aberrant overexpression of HOXA10 and miR-196b-5p by demethylation of the HOXA10 promoter, which provides a new perspective of TFF1/HOXA10/miR-196b-5p functions in human gastric cancer. Mol Cancer Res; 16(4); 696-706. ©2018 AACR.

Project description:BackgroundNitric oxide (NO) and cyclic guanosine phosphate (cGMP) play important roles in blood pressure regulation, neurotransmitter delivery, renal function, and tumorigenesis and development. The intermediate link of this signaling pathway, soluble guanylyl cyclase (sGC), is particularly important. However, the role of the GUCY1A2 gene encoding the sGC α2 subunit is unknown.MethodsGene expression and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. After screening for GUCY1A2 expression, the expression differences between gastric cancer (GC) tissues and adjacent noncancerous tissues were determined using R software. Quantitative real-time polymerase chain reaction (qRT-PCR) and meta-analysis were used to verify the result. The correlation between the expression of GUCY1A2 and clinicopathological parameters was explored by logistic regression. Then, Kaplan-Meier survival analysis and the Cox proportional hazards regression were used to evaluate the relationship between the expression of GUCY1A2 and the survival of GC patients. Finally, gene set enrichment analysis (GSEA) was used to explore and analyze the GC-related signaling pathways affected by high GUCY1A2 expression.ResultsWe found that GUCY1A2 was highly expressed in GC tissues compared to adjacent noncancerous tissues (P < 0.001). qRT-PCR (P < 0.001) and meta-analysis (SMD = 0.65, 95% CI: 0.20-1.10) confirmed the difference in GUCY1A2 expression. Logistic regression analysis showed that high expression of GUCY1A2 was associated with histological grade (OR=1.858 for poor vs. well or moderate, P = 0.004) and T stage (OR = 3.389 for T3 vs. T1, P = 0.025; OR = 3.422 for T4 vs. T1, P = 0.028). Kaplan-Meier curves indicated that GC patients with high expression of GUCY1A2 had a poor prognosis than that of patients with low expression. Univariate analysis indicated that GUCY1A2 and some clinicopathological parameters, such as age, pathological stage, and TNM stage, may predict poor prognosis. Multivariate analysis further confirmed that GUCY1A2 was an independent prognostic marker (HR = 1.699; 95%CI, 1.175-2.456; P = 0.005). GSEA showed that the high GUCY1A2 phenotype is significantly enriched for tumor-associated signaling pathways.ConclusionsGUCY1A2 is highly expressed in GC and may be used as a potential prognostic marker.

Project description:AimTo investigate the expression of myofibrillogenesis regulator-1 (MR-1) in relation to clinicopathological parameters and postoperative survival in a group of Chinese patients with gastric cancer.MethodsIn our previous study of human whole-genome gene expression profiling, the differentially expressed genes were detected in the gastric cancer and its adjacent noncancerous mucosa. We found that MR-1 was associated with the location and differentiation of tumors. In this study, MR-1 protein expression was determined by immunohistochemistry in specimens of primary cancer and the adjacent noncancerous tissues from gastric cancer patients. A set of real-time quantitative polymerase chain reaction assays based on the Universal ProbeLibrary-a collection of 165 presynthesized, fluorescence-labeled locked nucleic acid hydrolysis probes-was designed specifically to detect the expression of MR-1 mRNA. The correlation was analyzed between the expression of MR-1 and other tumor characteristics which may influence the prognosis of gastric cancer patients. A retrospective cohort study on the prognosis was carried out and clinical data were collected from medical records.ResultsMR-1 mRNA and protein could be detected in gastric cancer tissues as well as in matched noncancerous tissues. MR-1 was up-regulated at both mRNA (5.459 ± 0.639 vs 1.233 ± 0.238, P < 0.001) and protein levels (34.2% vs 13.2%, P = 0.003) in gastric cancer tissues. Correlation analysis demonstrated that high expression of MR-1 in gastric cancer was significantly correlated with clinical stage (P = 0.034). Kaplan-Meier analysis showed that the postoperative survival of the MR-1 positive group tended to be poorer than that of the MR-1 negative group, and the difference was statistically significant (P = 0.002). Among all the patients with stage I-IV carcinoma, the 5-year survival rates of MR-1 positive and negative groups were 50.40% and 12.70%, respectively, with respective median survival times of 64.27 mo (95%CI: 13.41-115.13) and 16.77 mo (95%CI: 8.80-24.74). Univariate and multivariate analyses were performed to compare the impact of MR-1 expression and other clinicopathological parameters on prognosis. In a univariate analysis on all 70 specimens, 6 factors were found to be significantly associated with the overall survival statistically: including MR-1 expression, depth of invasion, distant metastasis, lymph node metastasis, vascular invasion and the tumor node metastasis (TNM) stage based on the 7th edition of the International Union against Cancer TNM classification. To avoid the influence caused by univariate analysis, the expressions of MR-1 as well as other parameters were examined in multivariate Cox analysis. Clinicopathological variables that might affect the prognosis of gastric cancer patients were analyzed by Cox regression analysis, which showed that MR-1 expression and TNM stage were independent predictors of postoperative survival. The best mathematical multivariate Cox regression model consisted of two factors: MR-1 expression and TNM stage. Our results indicated that MR-1 protein could act as an independent marker for patient overall survival [Hazard ratio (HR): 2.215, P = 0.043].ConclusionMR-1 is an important variable that can be used to evaluate the outcome, prognosis and targeted therapy of gastric cancer patients.

Dataset Information

Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype.

Publications

Overexpression of miR-196b and HOXA10 characterize a poor-prognosis gastric cancer subtype.

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