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Upregulation of MiR-205 transcriptionally suppresses SMAD4 and PTEN and contributes to human ovarian cancer progression.

ABSTRACT: MicroRNAs (miRNAs) function as critical regulators of gene expression and their deregulation is associated with the development and progression of various cancers. This study aimed to investigate the biological role and mechanism of miR-205 in ovarian cancer (OC). MiR-205 was upregulated in OC tissues and cells in comparison to the controls. Meanwhile, overexpression of miR-205 was significantly associated with poor overall survival of OC patients. Functional study indicated that ectopic expression of miR-205 significantly promoted cell proliferation, migration, invasion and chemoresistance of OC cells. SMAD4 and PTEN were identified as direct targets of miR-205 using luciferase reporter assays, real-time PCR (qRT-PCR), and western blot. Most interestingly, in vivo studies indicated that miR-205 markedly promoted the growth and metastasis of tumors and the expression of miR-205 was also found to be inversely correlated with that of SMAD4 and PTEN in nude mice. Overall, we suggest that miR-205 functions as an oncogenic miRNA by directly binding to SMAD4 and PTEN, providing a novel target for the molecular treatment of ovarian cancer.

SUBMITTER: Li J

PROVIDER: S-EPMC5286557 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Upregulation of MiR-205 transcriptionally suppresses SMAD4 and PTEN and contributes to human ovarian cancer progression.

Li Juanni J Hu Kuan K Gong Guanghui G Zhu Ding D Wang Yixuan Y Liu Hailing H Wu Xiaoying X

Scientific reports 20170201

MicroRNAs (miRNAs) function as critical regulators of gene expression and their deregulation is associated with the development and progression of various cancers. This study aimed to investigate the biological role and mechanism of miR-205 in ovarian cancer (OC). MiR-205 was upregulated in OC tissues and cells in comparison to the controls. Meanwhile, overexpression of miR-205 was significantly associated with poor overall survival of OC patients. Functional study indicated that ectopic express ...[more]

PMID: 28145479

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Project description:BackgroundIn our previous investigation, we revealed a significant increase in the expression of microRNA-6881-3p (miR-6881-3p) in follicular fluid granulosa cells (GCs) from women with diminished ovarian reserve (DOR) compared to those with normal ovarian reserve (NOR). However, the role of miR-6881-3p in the development of DOR remains poorly understood.ObjectiveThis study aimed to elucidate the involvement of miR-6881-3p in the regulation of granulosa cells (GCs) function and the pathogenesis of DOR.Materials and methodsInitially, we assessed the expression levels of miR-6881-3p in GCs obtained from human follicular fluid in both NOR and DOR cases and explored the correlation between miR-6881-3p expression and clinical outcomes in assisted reproduction technology (ART). Bioinformatic predictions and dual-luciferase reporter assays were employed to identify the target gene of miR-6881-3p. Manipulation of miR-6881-3p expression was achieved through the transfection of KGN cells with miR-6881-3p mimics, inhibitor, and miRNA negative control (NC). Following transfection, we assessed granulosa cell apoptosis and cell cycle progression via flow cytometry and quantified target gene expression through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) analysis. Finally, we examined the correlation between target gene expression levels in GCs from NOR and DOR patients and their association with ART outcomes.ResultsOur findings revealed elevated miR-6881-3p levels in GCs from DOR patients, which negatively correlated with ovarian reserve function and ART outcomes. We identified a direct binding interaction between miR-6881-3p and the 3'-untranslated region of the SMAD4. Transfection with miR-6881-3p mimics induced apoptosis in KGN cell. Furthermore, miR-6881-3p expression negatively correlated with both mRNA and protein levels of the SMAD4. The mRNA and protein levels of SMAD4 were notably reduced in GCs from DOR patients, and SMAD4 mRNA expression positively correlated with ART outcomes. In addition, the mRNA levels of FSHR, CYP11A1 were notably reduced after transfection with miR-6881-3p mimics in KGN cell, while LHCGR notably increased. The mRNA and protein levels of FSHR, CYP11A1 were notably reduced in GCs from DOR patients, while LHCGR notably increased.ConclusionThis study underscores the role of miR-6881-3p in directly targeting SMAD4 mRNA, subsequently diminishing granulosa cell viability and promoting apoptosis, and may affect steroid hormone regulation and gonadotropin signal reception in GCs. These findings contribute to our understanding of the pathogenesis of DOR.

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Upregulation of MiR-205 transcriptionally suppresses SMAD4 and PTEN and contributes to human ovarian cancer progression.

Publications

Upregulation of MiR-205 transcriptionally suppresses SMAD4 and PTEN and contributes to human ovarian cancer progression.

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