Expression of alpha CP-4 inhibits cell cycle progression and suppresses tumorigenicity of lung cancer cells.
The protein alpha CP-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 alpha CP-4 may function as a lung tumor suppressor. Lack of alpha CP-4 expression is frequent in highly proliferative lung tumors and correlates with alpha CP-4 allele losses. The aim of this study was to evaluate the effect of alpha CP-4 on the tumorigenic capacity of lung cancer cells. alpha CP-4 expression was induced by transient transfection or stable infection with recombinant retroviruses. Induction of alpha CP-4 expression caused cell cycle arrest in G(2)/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 alpha CP-4 induction. Tumorigenicity of H1299 cells in nude mice was greatly inhibited by the expression of alpha CP-4. Moreover, induction of alpha CP-4 expression in already established tumors resulted in a sudden growth arrest. Immunocytochemistry analysis of the xenograft tumors revealed an in vivo effect of alpha CP-4 on cell proliferation and no effect on apoptosis. Finally, alpha CP-4 showed a subcellular localization different from alpha CP-4a, a splice variant that does not affect cell proliferation. In conclusion, expression of alpha CP-4 can inhibit proliferation and tumorigenesis of lung cancer cells, both in vivo and in vitro, by delaying the progression of the cell cycle.
Castaño
Zafira
Z
Division of Oncology, CIMA, University of Navarra, Pamplona, Spain.
Vergara-Irigaray
Nuria
N
Pajares
Maria J
MJ
Montuenga
Luis M
LM
Pio
Ruben
R
D000230:Adenocarcinoma / Q000378:metabolism; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002276:Carcinoid Tumor / Q000378:metabolism; D018287:Carcinoma, Large Cell / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002453:Cell Cycle; D002893:Chromosomes, Human, Pair 3; D004249:DNA Damage; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C411734:PCBP4 protein, human; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins