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MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells.

ABSTRACT: MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. Algorithm and microarray-based strategies identifies potential microRNA-101 targets. Among these, we validated EZH2, MCL-1 and FOS as direct targets of miR-101 and silencing of these genes mimics the tumor suppressive effects observed on promoting microRNA-101 function. Importantly, further results suggest an inverse correlation between low miR-101 and high EZH2, MCL-1 and FOS expression in EC specimens. We conclude that, as a crucial tumor suppressor, microRNA-101 suppresses cell proliferation, invasiveness and self-renewal in aggressive endometrial cancer cells via modulating multiple critical oncogenes. The microRNA-101-EZH2/MCL-1/FOS axis is a potential therapeutic target for endometrial cancer.

SUBMITTER: Konno Y

PROVIDER: S-EPMC4171612 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells.

Konno Yosuke Y Dong Peixin P Xiong Ying Y Suzuki Fumihiko F Lu Jiabin J Cai Muyan M Watari Hidemichi H Mitamura Takashi T Hosaka Masayoshi M Hanley Sharon J B SJ Kudo Masataka M Sakuragi Noriaki N

Oncotarget 20140801 15

MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migr ...[more]

PMID: 25153722

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Project description:Like telomere shortening, global DNA hypomethylation occurs progressively with cellular divisions or in vivo aging and functions as a mitotic clock to restrain malignant transformation/progression. Several DNA-methylation (DNAm) age clocks have been established to precisely predict chronological age using normal tissues, but show DNAm age drift in tumors, which suggests disruption of this mitotic clock during carcinogenesis. Little is known about DNAm age alterations and biological/clinical implications in endometrial cancer (EC). Here we address these issues by analyzing TCGA and GSE67116 cohorts of ECs. Horvath clock analysis of these tumors unexpectedly revealed that almost 90% of them exhibited DNAm age deceleration (DNAmad) compared to patient chronological age. Combined with an additional clock named Phenoage, we identified a subset of tumors (82/429) with high DNAmad (hDNAmad+) as assessed by both clocks. Clinically, hDNAmad+ tumors were associated with advanced diseases and shorter patient survival, compared to hDNAmad- ones. Genetically, hDNAmad+ tumors were characterized by higher copy number alterations (CNAs) whereas lower tumor mutation burden. Functionally, hDNAmad+ tumors were enriched with cell cycle and DNA mismatch repair pathways. Increased PIK3CA alterations and downregulation of SCGB2A1, the inhibitor of PI3K kinase, in hDNAmad+ tumors, might promote tumor growth/proliferation and stemness. In addition, the inactivation of aging drivers/tumor suppressors (TP53, RB1, and CDKN2A) while enhanced telomere maintenance occurred more frequently in hDNAmad+ tumors, which supports sustained tumor growth. Prominently, hDNAmad+ tumors were featured with immunoexclusion microenvironments, accompanied by significantly higher levels of VTCN1 expression while lower PD-L1 and CTLA4 expression, which indicates their poor response to immune checkpoint inhibitor (ICI)-based immunotherapy. We further showed significantly higher levels of DNMT3A and 3B expression in hDNAmad+ than in hDNAmad- tumors. Thus, the tumor suppressive function of aging-like DNA hypomethylation is severely impaired in hDNAmad+ tumors, likely due to enhanced expression of DNMT3A/3B and dysregulated aging regulators. Our findings not only enrich biological knowledge of EC pathogenesis but also help improve EC risk stratification and precision ICI immunotherapy.

Dataset Information

MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells.

Publications

MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells.

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