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Tumor suppressive role of microRNA-4731-5p in breast cancer through reduction of PAICS-induced FAK phosphorylation.

ABSTRACT: A wide array of microRNAs (miRNAs) is differentially expressed in breast tumors and also functions as tumor suppressors. Herein, the current study sought to unravel the function of miR-4731-5p in breast cancer progression. First, breast cancer-related miRNA and mRNA microarray data sets were retrieved for differential analyses. Subsequently, the expression patterns of miR-4731-5p, PAICS, and FAK in breast cancer tissues and cells were determined, in addition to analyses of their roles in glycometabolism, migration, invasion, epithelial-mesenchymal transition (EMT) analyzed through functional assays. Next, the targeting relation between miR-4731-5p and PAICS was validated. Xenograft tumors in nude mice were further established to reproduce and verify the in vitro findings. miR-4731-5p was poorly expressed and PAICS was highly expressed in breast cancer tissues and cells. PAICS was confirmed as a target of miR-4731-5p. Moreover, miR-4731-5p exerted an inhibitory effect on glycolysis, EMT, migration, and invasion in breast cancer cells via regulation of PAICS-dependent phosphorylation of FAK. In vivo assay further validated the significance of the miR-4731-5p/PAICS/FAK axis in vivo tumorigenesis and lung metastasis in breast cancer. Collectively, our findings indicated that miR-4731-5p inhibited breast cancer cell glycolysis and EMT through the reduction of PAICS-induced phosphorylation of FAK.

SUBMITTER: Lang L

PROVIDER: S-EPMC8980087 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Tumor suppressive role of microRNA-4731-5p in breast cancer through reduction of PAICS-induced FAK phosphorylation.

Lang Lei L Tao Jing J Yang Chaomei C Li Wei W

Cell death discovery 20220404 1

A wide array of microRNAs (miRNAs) is differentially expressed in breast tumors and also functions as tumor suppressors. Herein, the current study sought to unravel the function of miR-4731-5p in breast cancer progression. First, breast cancer-related miRNA and mRNA microarray data sets were retrieved for differential analyses. Subsequently, the expression patterns of miR-4731-5p, PAICS, and FAK in breast cancer tissues and cells were determined, in addition to analyses of their roles in glycome ...[more]

PMID: 35379785

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Project description:Aberrantly expressed microRNA (miRNA) are known to disrupt intracellular RNA networks in cancer cells. Exploring miRNA-dependent molecular networks is a major challenge in cancer research. In this study, we performed RNA-sequencing of breast cancer (BrCa) clinical specimens to identify tumor-suppressive miRNA in BrCa. In total, 64 miRNA were identified as candidate tumor-suppressive miRNA in BrCa cells. Analysis of our BrCa signature revealed that several miRNA duplexes (guide strand/passenger strand) derived from pre-miRNA were downregulated in BrCa tissues (e.g. miR-99a-5p/-3p, miR-101-5p/-3p, miR-126-5p/-3p, miR-143-5p/-3p, and miR-144-5p/-3p). Among these miRNA, we focused on miR-101-5p, the passenger strand of pre-miR-101, and investigated its tumor-suppressive roles and oncogenic targets in BrCa cells. Low expression of miR-101-5p predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0316). Ectopic expression of miR-101-5p attenuated aggressive phenotypes, e.g. proliferation, migration, and invasion, in BrCa cells. Finally, we identified seven putative oncogenic genes (i.e. High Mobility Group Box 3, Epithelial splicing regulatory protein 1, GINS complex subunit 1 (GINS1), Tumor Protein D52, Serine/Arginine-Rich Splicing Factor Kinase 1, Vang-like protein 1, and Mago Homolog B) regulated by miR-101-5p in BrCa cells. The expression of these target genes was associated with the molecular pathogenesis of BrCa. Furthermore, we explored the oncogenic roles of GINS1, whose function had not been previously elucidated, in BrCa cells. Aberrant expression of GINS1 mRNA and protein was observed in BrCa clinical specimens, and high GINS1 expression significantly predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0126). Knockdown of GINS1 inhibited the malignant features of BrCa cells. Thus, identification of tumor-suppressive miRNA and molecular networks controlled by these miRNA in BrCa cells may be an effective strategy for elucidation of the molecular pathogenesis of this disease.

Dataset Information

Tumor suppressive role of microRNA-4731-5p in breast cancer through reduction of PAICS-induced FAK phosphorylation.

Publications

Tumor suppressive role of microRNA-4731-5p in breast cancer through reduction of PAICS-induced FAK phosphorylation.

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