J Cancer 2021; 12(12):3418-3426. doi:10.7150/jca.51849

Research Paper

Acidic extracellular pH induces autophagy to promote anoikis resistance of hepatocellular carcinoma cells via downregulation of miR-3663-3p

Siying Wang1*, Yuanyuan Lv1*, Yangyang Zhou1, Jing Ling1, Hui Wang1, Dishui Gu2, Cun Wang1, Wenxin Qin1, Xingling Zheng1✉, Haojie Jin1✉

1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 25/Ln 2200 Xie-Tu Road, Shanghai 200032, China.
2. Department of Pathophysiology, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, Guangdong, 523808, China.
*These authors contributed equally to this work.

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Citation:
Wang S, Lv Y, Zhou Y, Ling J, Wang H, Gu D, Wang C, Qin W, Zheng X, Jin H. Acidic extracellular pH induces autophagy to promote anoikis resistance of hepatocellular carcinoma cells via downregulation of miR-3663-3p. J Cancer 2021; 12(12):3418-3426. doi:10.7150/jca.51849. Available from https://www.jcancer.org/v12p3418.htm

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Abstract

Metastasis is the major reason for poor prognosis and high fatality in hepatocellular carcinoma (HCC). Due to the “Warburg effect”, an acidic tumor microenvironment (TME) exists in solid tumors and plays a critical role in cancer metastasis. Thus, clarifying the mechanism underlying the acidic TME in tumor metastasis could facilitate the development of new therapeutic strategies for HCC. Anoikis resistance is one of the most important events in the early stage of cancer metastasis. Here, we report that acidic extracellular pH (pHe) promotes autophagy of HCC cells via the AMPK/mTOR pathway. We found that autophagy induced by acidity enhances anoikis resistance of HCC cells, which could be reversed by autophagy inhibitors. Furthermore, miR-3663-3p was downregulated by acidity, and overexpression of miR-3663-3p abolished acidic pHe-induced autophagy and anoikis resistance. In summary, acidic pHe enhances anoikis resistance of HCC cells by inducing autophagy, which is regulated by miR-3663-3p. Our findings provide new insight into how the acidic TME is involved in HCC progression.

Keywords: hepatocellular carcinoma, acidic tumor microenvironment, anoikis resistance, autophagy, miR-3663-3p