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miR-212 and mTOR form a regulation loop to modulate autophagy in colorectal adenoma HT-29 cells.
Discovery Medicine 2018 June
Autophagy is a conserved lysosomal degradation pathway that regulates cell survival and death in order to maintain cellular homeostasis. Dysfunctional autophagy is associated with different types of cancer, making it an attractive therapeutic target. Mammalian target of rapamycin (mTOR) signaling negatively regulates autophagy and suppresses the efficacy of certain cancer therapeutic agents. NVP-BEZ235 is a dual inhibitor of the PI3K/mTOR signaling pathway and exhibits anti-cancer activities; it also induced autophagy and inhibited proliferation in colorectal adenoma HT-29 cells. Colorectal adenoma and colorectal cancer have been recently shown to have elevated levels of miR-212. In the current study, we examined the role of miR-212 in NVP-BEZ235-induced autophagy in HT-29 cells. NVP-BEZ235 at the concentration as low as of 1 nM effectively induced autophagy and dose-dependently inhibited the expression of microRNA-212 (miR-212) whereas mTOR activator MHY1485 elevated the miR-212 expression. Transfection of miR-212 mimics inhibited autophagy whereas miR-212 inhibitors promoted autophagy as assessed by the LC3B-I conversion to LC3B-II and the expression levels of beclin-1. Furthermore, miR-212 mimics activated mTOR whereas miR-212 inhibitors suppressed mTOR activation as shown by the levels of phospho-mTOR. miR-212 mimics further enhanced the effect of NVP-BEZ235 in reducing the viability of HT-29 cells. Our data support that miR-212 is a target of mTOR signaling as well as an activator of mTOR to negatively regulate autophagy. Thus, miR-212 and mTOR signalings may form a positive regulation loop in maintaining cellular homeostasis. This study warrants further investigation of miR-212 as an effective target of autophagy-based cancer therapeutic strategies.
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