NFIB controls chemosensitivity in small cell lung cancer by suppressing Notch signaling activity

Background: Small cell lung cancer(SCLC) is a highly aggressive malignant tumor type, characterized by universal acquired therapeutic resistance during rapidly recurrence. However, we have a poor understanding of the mechanisms underlying development of resistance. NFIB is a bona fide oncogene in SCLC with effects on proliferation, invasion, and apoptosis inhibition. Methods: The expression of NFIB and related genes was evaluated in SCLC cells and tissue specimens, by western blot, RT-PCR immunofluorescence and immunohistochemistry. The relationship between genes was verified by ChIP-PCR experiments. CCK8 assays was used for drug resistance experiments. Results: NFIB is highly correlated with NE markers and may be participated in the generating of tumor heterogeneity mediated in part by Notch1. The suppressive effect of NFIB on Notch1 is relieved and led to NE gene inhibiting when SCLC cells lack of NFIB. These cells are slow growing and also relatively chemoresistant. Importantly, Notch blockade in combination with chemotherapy alleviates the formation of intratumoral heterogeneity and enhances chemosensitivity. Conclusions: NFIB can be both tumor-pro-tumorigenic and chemosensitizing in SCLC. NFIB knockdown results in endogenous activation of the Notch pathway. These results uncover the dual character of oncogene as NFIB in SCLC and offer perspectives for efficacious combination therapies that might also hold promise for treating human SCLC.