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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Yosuke Konno1,*, Peixin Dong2,*, Ying Xiong3,*, Fumihiko Suzuki4,*, Jiabin Lu5, Muyan Cai5, Hidemichi Watari1, Takashi Mitamura1, Masayoshi Hosaka1, Sharon J. B. Hanley2, Masataka Kudo1 and Noriaki Sakuragi1,2
1 Department of Gynecology, Hokkaido University, Sapporo, Japan
2 Department of Women’s Health Educational System, Hokkaido University, Sapporo, Japan
3 Department of Gynecology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
4 Department of Obstetrics and Gynecology, Tohoku University, Sendai, Japan
5 Department of Pathology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China
* These authors contributed equally to this work
Peixin Dong, email:
Noriaki Sakuragi, email:
Keywords: microRNA-101, proliferation, EMT, EZH2, MCL-1, FOS
Received: May 30, 2014 Accepted: July 1, 2014 Published: July 2, 2014
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.
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