Tac2-N acts as a novel oncogene and promotes tumor metastasis via activation of NF-\u03baB signaling in lung cancer

Abstract

BackgroundHigh rates of recurrence and metastasis are the major cause of the poor outcomes for patients with lung cancer. In previous research, we have demonstrated that Tac2-N promotes tumor growth by suppressing p53 signaling in lung cancer. Beyond that, other biological functions and clinical significance of Tac2-N in lung cancer progression are still unknown.MethodsTissue microarrays of 272 lung cancer patients were constructed to assess the association of Tac2-N expression and prognosis of lung cancer patients with different clinical stages. The protein expression of Tac2-N in metastatic and non-metastatic specimens were detected by IHC. In vitro migration and invasion and in vivo nude mice metastasis model were used to evaluate the effect of Tac2-N ectopic expression on metastasis capability of lung cancer cells. The downstream signaling pathway of Tac2-N was explored using luciferase reporter assays and WB.ResultsThe expression of Tac2-N was associated with advanced stages, but not with early stages (P = 0.513). Tac2-N expression is sharply overexpressed in metastatic tumors compared with non-metastatic tumors. In vitro and in vivo assays suggested that Tac2-N facilitated migration and invasion of lung cancer cells in vitro and promoted tumor metastasis in vivo. Mechanistically, Tac2-N increased the degradation of IκB by promoting its phosphorylation, and subsequently activated NF-κB activity by facilitating the nuclear translocation of NF-κB and stimulating the transcription of targets, MMP7 and MMP9. Notably, the C2B domain of Tac2-N was crucial for Tac2-N to activate NF-κB signal. Blockage of NF-κB by shRNA or inhibitor attenuates the function of Tac2-N in the promotion of metastasis.ConclusionsOur study provided proof of principle to show that Tac2-N serves as a novel oncogene gene and plays an important role in the progression and metastasis of lung cancer.