Fatty acid synthase is a primary target of MiR-15a and MiR-16-1 in breast cancer
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Jingxuan Wang1,3, Xiao Zhang2, Jinming Shi2, Paul Cao3, Meimei Wan3, Qiang Zhang3, Yunxuan Wang1, Steven J. Kridel3, Wennuan Liu4, Jianfeng Xu3,4, Qingyuan Zhang1, Guangchao Sui2,3
1Department of Medical Oncology, the Third Affiliated Hospital of Harbin Medical University, Harbin P. R. China
2College of Life Science, Northeast Forestry University, Harbin, China
3Department of Cancer Biology and Comprehensive Cancer Center
4Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem
Qingyuan Zhang, email: firstname.lastname@example.org
Keywords: Fatty acid synthase (FASN), miR-15a and miR-16-1, 3’-UTR, breast cancer, gene expression
Received: December 13, 2015 Accepted: September 26, 2016 Published: October 05, 2016
Fatty acid synthase (FASN) is upregulated in breast cancer and correlates with poor prognosis. FASN contributes to mammary oncogenesis and serves as a bona fide target in cancer therapies. MicroRNAs inhibit gene expression through blocking mRNA translation or promoting mRNA degradation by targeting their 3’-UTRs. We identified four microRNAs in two microRNA clusters miR-15a-16-1 and miR-497-195 that share a common seed sequence to target the 3′-UTR of the FASN mRNA. In reporter assays, both of these microRNA clusters inhibited the expression of a reporter construct containing the FASN 3’-UTR. However, only ectopic miR-15a-16-1, but not miR-497-195, markedly reduced the levels of endogenous FASN in breast cancer cells. Both miR-15a and miR-16-1 contributes to inhibiting FASN expression and breast cancer cell proliferation. Consistently, a sponge construct consisting of eight repeats of the FASN 3’-UTR region targeted by these microRNAs could markedly increase endogenous FASN levels in mammary cells. When FASN expression was restored by ectopic expression in breast cancer cells, retarded cell proliferation caused by miR-15a-16-1 was partially rescued. In conclusion, we demonstrated that FASN expression is primarily downregulated by miR-15a and miR-16-1 in mammary cells and FASN is one of the major targets of these two tumor suppressive microRNAs.
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