Journal
JOURNAL OF CANCER
Volume 12, Issue 12, Pages 3418-3426Publisher
IVYSPRING INT PUBL
DOI: 10.7150/jca.51849
Keywords
hepatocellular carcinoma; acidic tumor microenvironment; anoikis resistance; autophagy; miR-3663-3p
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Funding
- National Natural Science Foundation of China [81702838, 82073039, 82011530441]
- Shanghai RisingStar Program [19QA1408200]
- Shanghai Municipal Commission of Health and Family Planning [2018YQ20, 201640055]
- Shanghai Natural Science Foundation [19ZR1452700]
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The acidic tumor microenvironment (TME) promotes autophagy of HCC cells via the AMPK/mTOR pathway, enhancing anoikis resistance. This process is regulated by miR-3663-3p, providing new insights into HCC progression involving the acidic TME.
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(e)) 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(e)-induced autophagy and anoikis resistance. In summary, acidic pH(e) 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.
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