Proinflammatory TIFA-NF-κB axis drives intrinsic survival signaling and acquires macrophage niches via DAMPs to promote HCC resistance to sorafenib

Sorafenib is the first-line treatment for advanced stage hepatocellular carcinoma (HCC), but rapid disease re-progression occurs in most treated cases, with molecular mechanism remaining elusive. The resistance to sorafenib has been correlated with inflammation, and here we investigated how the pro-inflammatory TIFA signaling modulates the inflammatory tumor microenvironment to negate sorafenib cytotoxicity and prime for HCC dissemination. We found that the TIFA-NF-κB axis in HCC cells compromised sorafenib cytotoxicity in alliance with pro-tumor M2 macrophages, suggesting an intensive crosstalk between HCCs and M2 macrophages. To identify the key mediators of such crosstalk between HCC cells and macrophages underlying sorafenib resistance, primary macrophages were cocultured with HCC cells and then subjected to targeted RNA-panels for transcriptome analysis of innate immune and inflammatory factors. 6 samples. Mahlavu cells were transfected with control siRNA or TIFA siRNA and then treated with sorafenib. Treated cells were respectively cocultured with M0, M1, and M2 macrophages. Total RNAs of these macrophages were thus subjected to targeted RNA-seq transcriptome analysis using QIAGEN Human Inflammation and Immunity Transcriptome RNA targeted panel (Cat#333002 RHS-005Z).