Insufficient radiofrequency ablation drives hepatocellular carcinoma progression by activating of UPRmt

Abstract

Mitochondrial-unfolded protein response (UPR^mt) plays an important role in acute stress response and tumor progression. Sublethal heat stress from insufficient radiofrequency ablation (IRFA) has been confirmed to promote hepatocellular carcinoma (HCC) progression. However, whether UPR^mt is involved in IRFA-induced HCC recurrence and metastasis remains unknown. Here, we detected higher level of UPR^mt-related proteins in human HCC tissues than adjacent tissues. In addition, both IRFA and sublethal heat stress can promote the expression of UPR^mt-related proteins in HCC cells in vivo and in vitro. Knockdown of HSP60 with short hairpin RNA (shRNA) can effectively inhibit the activation of UPR^mt. Inhibit the activation of UPR^mt, inhibit the migration and invasion of HCC cells mediated by IRFA, and also inhibit the growth of subcutaneous tumor in nude mice. Mechanistically, we found that activated transcription factor 5 (ATF5) is the key factor to activate UPR^mt by IRFA. IRFA promotes the expression of ATF5 in HCC cells. Knockdown of ATF5 inhibits the activation of UPR^mt mediated by IRFA. Besides, silent ATF5 also inhibits IRFA-mediated progression of HCC. Collectively, these findings reveal a novel mechanism for IRFA promoting the progression of HCC. It provides experimental basis for further studying of IRFA promoting tumor recurrence and metastasis and developing corresponding clinical treatment strategies.