Most lung cancer patients are diagnosed late with metastasis, which is the major cause of cancer-related death and recurrent tumors that often exhibit chemoresistance. In the present study, we initially identified gap junction beta-4 protein (Gjb4) to be overexpressed in highly metastatic cancer cells selected by their enhanced binding to serum components. Overexpression or knockdown of Gjb4 increased or decreased lung metastasis of syngeneic mice, respectively. We found that Gjb4 expression was higher in lung tumors than normal tissues (p = 0.0026), and Gjb4 levels in blood buffy coat samples showed significant performance in diagnosing stage I–III (p = 0.002814) and stage IV (p < 0.0001) lung cancer. Moreover, high Gjb4 expression levels were correlated with poor prognosis (p = 1.4e−4) and recurrence (p = 1.9e−12). Using syngeneic mouse model, we observed that Gjb4 was able to promote tumor growth. High molecular weight serum fraction containing the major growth factor component IGF1 was able to induce Gjb4 via PKC pathway. Gjb4 activated Src signaling via MET, and overexpression of Gjb4 enhanced sphere-forming ability and anchorage-independent growth, which were reversed by inhibition of Src. In addition, we demonstrated that Gjb4-mediated Src activation enhanced chemoresistance of cancer cells toward gemcitabine and etoposide. The combination of Gjb4 knockdown, gemcitabine, and dasatinib further enhanced the inhibition of cancer cell viability. Together, our study has identified Gjb4 as a potential novel diagnostic and prognostic biomarker for lung cancer. Targeting Gjb4 may be exploited as a modality for improving lung cancer therapy.
