Cytoplasmic fragment of CD147 generated by regulated intramembrane proteolysis contributes to HCC by promoting autophagy.

Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers worldwide. CD147 (EMMPRIN or basigin) is a leading gene relating to hepatocarcinogenesis and metastasis, and is detected in transmembrane, exosome or circulating forms in HCC patients. The endosome recycling of CD147 further enhances the function of this oncoprotein from a dynamic perspective. However, previous studies about CD147 mainly focused on one separate form, and little attention has been paid to how the different forms of tumor-derived CD147 changes. Moreover, uncovering the roles of the residual C-terminal portion of CD147 after shedding is inevitable to fully understand CD147 promoting tumor progression. In this study, we discovered that under low-cholesterol condition, CD147 endocytosis is inhibited but its shedding mediated by ADAM10 is enhanced. Further procession of residual CD147 in the lysosome produces nuclear-localized CD147-ICD (intracellular domain of CD147), which contributes to autophagy through NF-κB-TRAIL-caspase8-ATG3 axis. As autophagy endows cancer cells with increased adaptability to chemotherapy, and HAb 18 (a specific antibody targeting CD147) inhibits CD147 shedding and sequential CD147-ICD enhances autophagy, we found the combination of HAb 18 and cisplatin exhibited marked antitumor efficiency.