Oncoprotein HBXIP promotes tumorigenesis through MAPK/ERK pathway activation in non-small cell lung cancer.

Objective: The oncoprotein, hepatitis B X-interacting protein (HBXIP), has been reported to play an important role in humanmalignancies. However, its functions in non-small cell lung cancer (NSCLC) are poorly understood. The goal of the present studywas to identify the role of HBXIP in the regulation of NSCLC development. Methods: The level of HBXIP expression in NSCLC tissue was assessed by immunohistochemical and Western blot analyses, andits relationships with clinicopathological features and outcomes were statistically evaluated. The effects of HBXIP on NSCLC cellprogression were assessed through cell viability, colony formation, and flow cytometry analyses in vitro. The mechanism by whichHBXIP regulated the MAPK pathway was studied by Western blot, immunofluorescence, and immunoprecipitation assays. Inaddition, in vivo experiments were performed to evaluate the progression of NSCLC and ERK signaling pathway activation afterHBXIP knockdown. Results: HBXIP was overexpressed in human NSCLC and was correlated with the invasiveness of NSCLC. The high expressionof HBXIP in NSCLC was significantly correlated with gender (P = 0.033), N stage (P = 0.002), and tumor-node-metastasis stage(P = 0.008). In vitro experiments using an NSCLC cell line revealed that HBXIP knockdown resulted in the suppression of cellproliferation and colony formation, which was consistent with the enhanced cell cycle arrest in G1 phase. The results of a mechanisticinvestigation suggested that binding of HBXIP to MEK1 protein promoted MAPK/ERK signaling pathway activation in NSCLC bypreventing the proteasome-mediated degradation of MEK1. In addition, the results obtained using in vivo subcutaneous tumorxenografts confirmed that HBXIP deficiency decreased MEK1 protein levels and NSCLC tumor growth. Conclusions: Taken together, our results showed that the HBXIP-MEK interaction promoted oncogenesis via the MAPK/ERKpathway, which may serve as a novel therapeutic target for cancers in which MAPK/ERK signaling is a dominant feature.