Wang Siying, Lv Yuanyuan, Zhou Yangyang, Ling Jing, Wang Hui, Gu Dishui, Wang Cun, Qin Wenxin, Zheng Xingling, Jin Haojie
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.
Department of Pathophysiology, School of Basic Medical Sciences, Guangdong Medical University, Dongguan, Guangdong, 523808, China.
J Cancer. 2021 Apr 19;12(12):3418-3426. doi: 10.7150/jca.51849. eCollection 2021.
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 (pH) 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 pH-induced autophagy and anoikis resistance. In summary, acidic pH 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.
转移是肝细胞癌（HCC）预后不良和高死亡率的主要原因。由于“瓦伯格效应”，实体瘤中存在酸性肿瘤微环境（TME），其在癌症转移中起关键作用。因此，阐明肿瘤转移中酸性TME的潜在机制有助于开发针对HCC的新治疗策略。失巢凋亡抗性是癌症转移早期最重要的事件之一。在此，我们报告酸性细胞外pH值（pH）通过AMPK/mTOR途径促进HCC细胞的自噬。我们发现酸度诱导的自噬增强了HCC细胞的失巢凋亡抗性，而自噬抑制剂可逆转这种抗性。此外，miR-3663-3p在酸性条件下表达下调，miR-3663-3p的过表达消除了酸性pH诱导的自噬和失巢凋亡抗性。总之，酸性pH通过诱导自噬增强HCC细胞的失巢凋亡抗性，而自噬受miR-3663-3p调控。我们的研究结果为酸性TME如何参与HCC进展提供了新的见解。
