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MicroRNA-222-3p/GNAI2/AKT axis inhibits epithelial ovarian cancer cell growth and associates with good overall survival.

ABSTRACT: Ovarian carcinoma is the most lethal gynecologic tumor worldwide. Despite having developed molecular diagnostic tools and targeted therapies over the past few decades, patient survival is still quite poor. Numerous studies suggest that microRNAs are key regulators of many fundamental biological processes, including neoplasia and tumor progression. miR-222 is one of those miRNAs that has attracted much attention for its multiple roles in human diseases, especially cancer. The potential role of microRNAs in ovarian cancer has attracted much attention in recent years. Some of these microRNAs have been suggested as potential therapeutic targets for EOC patients. In this study, we sought to investigate the biologic functions of miR-222-3p in EOC carcinogenesis. Herein, we examined the expression of miR-222-3p in EOC patients, mouse models and cell lines, and found that higher expression of miR-222-3p was associated with better overall survival in EOC patients, and its level was negatively correlated with tumor growth in vivo. Furthermore, in-vitro experiments indicated that miR-222-3p inhibited EOC cell proliferation and migration, and decreased the phosphorylation of AKT. We identified GNAI2 as a target of miR-222-3p. We also found that GNAI2 promoted EOC cell proliferation, and is an activator of the PI3K/AKT pathway. We describe the characterization of a novel regulatory axis in ovarian cancer cells, miR-222-3p/GNAI2/AKT and its potential application as a therapeutic target for EOC patients.

SUBMITTER: Fu X

PROVIDER: S-EPMC5348346 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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MicroRNA-222-3p/GNAI2/AKT axis inhibits epithelial ovarian cancer cell growth and associates with good overall survival.

Fu Xiaodan X Li Yimin Y Alvero Ayesha A Li Juanni J Wu Qihui Q Xiao Qing Q Peng Yulong Y Hu Yongbin Y Li Xiang X Yan Wenguang W Guo Ke K Zhou Wenjuan W Wang Yong Y Liu Junwen J Zhang Yu Y Mor Gil G Wen Jifang J Yin Gang G

Oncotarget 20161201 49

Ovarian carcinoma is the most lethal gynecologic tumor worldwide. Despite having developed molecular diagnostic tools and targeted therapies over the past few decades, patient survival is still quite poor. Numerous studies suggest that microRNAs are key regulators of many fundamental biological processes, including neoplasia and tumor progression. miR-222 is one of those miRNAs that has attracted much attention for its multiple roles in human diseases, especially cancer. The potential role of mi ...[more]

PMID: 27811362

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Project description:Ovarian cancer (OC), the eighth-leading cause of cancer-related death among females worldwide, is mainly represented by epithelial OC (EOC) that can be further subdivided into four subtypes: serous (75%), endometrioid (10%), clear cell (10%), and mucinous (3%). Major reasons for high mortality are the poor biological understanding of the OC mechanisms and a lack of reliable markers defining each EOC subtype. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression primarily by targeting messenger RNA (mRNA) transcripts. Their aberrant expression patterns have been associated with cancer development, including OC. However, the role of miRNAs in tumorigenesis is still to be determined, mainly due to the lack of consensus regarding optimal methodologies for identification and validation of miRNAs and their targets. Several tools for computational target prediction exist, but false interpretations remain a problem. The experimental validation of every potential miRNA-mRNA pair is not feasible, as it is laborious and expensive. In this study, we analyzed the correlation between global miRNA and mRNA expression patterns derived from microarray profiling of 197 EOC patients to identify the signatures of miRNA-mRNA interactions associated with overall survival (OS). The aim was to investigate whether these miRNA-mRNA signatures might have a prognostic value for OS in different subtypes of EOC. The content of our cohort (162 serous carcinomas, 15 endometrioid carcinomas, 11 mucinous carcinomas, and 9 clear cell carcinomas) reflects a real-world scenario of EOC. Several interaction pairs between 6 miRNAs (hsa-miR-126-3p, hsa-miR-223-3p, hsa-miR-23a-5p, hsa-miR-27a-5p, hsa-miR-486-5p, and hsa-miR-506-3p) and 8 mRNAs (ATF3, CH25H, EMP1, HBB, HBEGF, NAMPT, POSTN, and PROCR) were identified and the findings appear to be well supported by the literature. This indicates that our study has a potential to reveal miRNA-mRNA signatures relevant for EOC. Thus, the evaluation on independent cohorts will further evaluate the performance of such findings.

Project description:Background: Epithelial ovarian cancer (EOC) is one of the most lethal malignancies in women worldwide. Many studies showed the transcription factor SNAI2-induced Epithelial-Mesenchymal Transition (EMT) through inhibiting E-cadherin (E-cad) expression. Our previous study reported that miR-222-3p was an important tumor-suppressive miRNA for EOC development and dissemination. The present study aimed to acquire a deeper mechanistic understanding of the role of miR-222-3p regulation that might contribute to improving current anti-metastasis strategies in EOC. Methods: A variety of techniques were used to measure mRNA and protein expression levels, including quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, immunohistochemical (IHC) staining, and immunofluorescence (IF). Four different microRNA (miRNA) target prediction databases were used to predict the target genes of miR-222. Luciferase assay was performed to determine the direct binding of miR-222-3p to the untranslated region (3'-UTR) of PDCD10. The biological effects of PDCD10 and miR-222-3p were also investigated in vitro by Transwell and wound healing assays, as well as in vivo by a xenograft mice model. Combining UCSC and JASPAR, as well as ENCODE public databases, we predicted that the transcription factor SNAI2 could affect miR-222-3p expression. Luciferase assay was utilized to examine the validity of putative SNAI2 binding sites for miR-222-3p regulation. Chromatin immunoprecipitation (ChIP) was used to explore the SNAI2's occupancy on the miR-222-3p promoter. Results: We observed the inhibitory effect of SNAI2 on miR-222-3p transcription and confirmed the tumor-suppressive function of miR-222-3p both in EOC cells and tissues. PDCD10 was upregulated and inversely correlated with miR-222-3p, both in vitro and in vivo, which was consistent with the information in bioinformatics databases. Furthermore, We observed direct binding of miR-222-3p to the 3'-UTR of PDCD10 and inhibition of PDCD10 translation, which, in turn, inhibited EOC cell migration in vitro and repressed EOC xenografted tumor metastasis in vivo. We found that genetic overexpression of PDCD10 (OE-PDCD10) increased cancer metastasis by down-regulating E-cad and enhancing Vimentin (VIM) thereby inducing EMT and promoting β-catenin/Wnt-mediated cell migration.

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MicroRNA-222-3p/GNAI2/AKT axis inhibits epithelial ovarian cancer cell growth and associates with good overall survival.

Publications

MicroRNA-222-3p/GNAI2/AKT axis inhibits epithelial ovarian cancer cell growth and associates with good overall survival.

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