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The protein αCP-4 (also known as hnRNP E4) is an RNA binding protein encoded by a gene at 3p21, one of the most common altered regions in lung cancer. It has been proposed that αCP-4 may function as a lung tumor suppressor. Lack of αCP-4 expression is frequent in highly proliferative lung tumors and correlates with αCP-4 allele losses. The aim of this study was to evaluate the effect of αCP-4 on the tumorigenic capacity of lung cancer cells. αCP-4 expression was induced by transient transfection or stable infection with recombinant retroviruses. Induction of αCP-4 expression caused cell cycle arrest in G2/M in 3 out of the 7 lung cancer cell lines studied, while no effect on apoptosis was observed. Anchorage-independent growth and invasion capacity of H1299 cells were significantly reduced by αCP-4 induction. Tumorigenicity of H1299 cells in nude mice was greatly inhibited by the expression of αCP-4. Moreover, induction of αCP-4 expression in already established tumors resulted in a sudden growth arrest. Immunocytochemistry analysis of the xenograft tumors revealed anin vivoeffect of αCP-4 on cell proliferation and no effect on apoptosis. Finally, αCP-4 showed a subcellular localization different from αCP-4a, a splice variant that does not affect cell proliferation. In conclusion, expression of αCP-4 can inhibit proliferation and tumorigenesis of lung cancer cells, bothin vivoandin vitro, by delaying the progression of the cell cycle.