OncoTargets and Therapy (Apr 2019)
Retinoic acid receptor α facilitates human colorectal cancer progression via Akt and MMP2 signaling
Abstract
Gui-Li Huang,1 Qing-Xi Chen,2 Jia-Jia Ma,1 Si-Yao Sui,1 Yu-Ning Wang,1 Dong-Yan Shen31Agricultural Product Storage and Processing Laboratory, Suzhou Academy of Agricultural Sciences, Suzhou, 215155, People’s Republic of China; 2State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361102, People’s Republic of China; 3Biobank, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People’s Republic of ChinaPurpose: Retinoic acid α (RARα) is overexpressed in various tumors and facilitates cancer progression. Although RARα has been shown to facilitate colorectal cancer (CRC) progression, more efforts to characterize mechanisms of RARα in CRC are needed in order to develop better target-based drugs for tumor therapy. Methods: RARα expression in CRC was assessed by IHC. EdU, QPCR, Western blotting, dual-luciferase reporter assay and ChIP were performed to explore the role of RARα in CRC and the mechanism involoved.Results: Here, we show an overexpression of RARα in 73.5% (i.e., 25 of 34 human CRC specimens). RARα knockdown decreased cell proliferation, migration, and invasion. Such phenotypic manifestations can be correlated to lowered activation of Akt and expression of PCNA (proliferating cell nuclear antigen) as well as MMP2 (matrix metallopeptidase). Mechanistically, RARα facilitates CRC growth through Akt signaling activation to cause levels of PCNA to be upregulated. Furthermore, RARα promotes migration and invasion of CRC cells by directly recruiting the MMP2 promoter to enhance the expression of MMP2.Conclusions: These findings demonstrate that CRC carcinogenesis is promoted by RARα via an enhanced Akt signaling and by increasing MMP2 transcription. CRC therapy can examine the use of RARα as a prospective molecular target.Keywords: colorectal cancer, RARα, proliferation, PCNA, MMP2
