A Positive Feedback Loop of AKR1C3-Mediated Activation of NF-?B and STAT3 Facilitates Proliferation and Metastasis in Hepatocellular Carcinoma

Abstract AKR1C3 is an enzyme belonging to the aldo-ketoreductase family, members of which catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. plays important role tumor progression metastasis, however, little known about function molecular mechanism underlying hepatocellular carcinoma (HCC). In this study, we report that significantly upregulated HCC increased associated with poor survival. positively regulated cell proliferation metastasis vitro vivo. promoted by activating NF-?B signaling. Furthermore, activity modulating TRAF6 inducing its autoubiquitination cells. Activation released proinflammatory factors facilitated phosphorylation STAT3 invasion. Gain- loss-of-function experiments showed invasion via IL6/STAT3 pathway. also directly bound promoter transcription AKR1C3, thereby establishing a positive regulatory feedback loop. Treatment inhibitors indocin medroxyprogesterone acetate inhibited growth apoptosis Collectively, these results indicate AKR1C3/NF-?B/STAT3 signaling loop could be promising therapeutic target HCC. Significance: These findings elucidate novel AKR1C3-driven regulates HCC, providing potential prognostic targets disease.