Transcriptional regulation of NDUFA4L2 by NFIB induces sorafenib resistance via decreasing ROS in HCC.

Sorafenib is one of the first-line therapeutic drugs for advanced hepatocellular carcinoma (HCC). However, only 30% patients can benefit from sorafenib due to drug resistance. We and other groups have revealed that nuclear factor I B (NFIB) regulates liver regeneration and carcinogenesis, but its role in drug resistance is poorly known. We found that NFIB was up-regulated in sorafenib-resistant SMMC-7721 cells compared to parental cells. NFIB knockdown not only sensitized drug-resistant cells to sorafenib, but also inhibited proliferation and invasion of these cells. Meanwhile, NFIB promoted the proliferation, invasion of HCC cells in vitro, and facilitated tumor growth and metastasis in vivo. Knocking down NFIB synergetically inhibited tumor growth with sorafenib. Mechanically, gene expression profiling and subsequent verification experiments proved that NFIB could bind with the promoter region of a complex I inhibitor NDUFA4L2 and promote its transcription. Transcriptional up-regulation of NDUFA4L2 by NFIB could thus inhibit the sorafenib-induced reactive oxygen species accumulation. Finally, we found that NFIB was highly expressed in HCC tissues, and high NFIB expression level was associated with macrovascular invasion, advanced tumor stage and poor prognosis of HCC patients (n=156). In summary, we demonstrated that NFIB could transcriptionally up-regulate NDUFA4L2 to enhance both intrinsic and acquired sorafenib resistance of HCC cells via reducing ROS induction.