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CP-4, Encoded by a Putative Tumor Suppressor Gene at 3p21, But Not Its Alternative Splice Variant CP-4a, Is Underexpressed in Lung Cancer

¹ Division of Oncology and Departments of ² Biochemistry, ³ Genetics, ⁴ Histology and Pathology, and ⁵ Biotechnology, Clinica Universitaria and School of Medicine, Center for Applied Medical Research. University of Navarra. Pamplona, Spain

CP-4 is an RNA-binding protein coded by PCBP4, a gene mapped to 3p21, a common deleted region in lung cancer. In this study we characterized the expression of CP-4 and CP-4a, an alternatively spliced variant of CP-4, in lung cancer cell lines and non-small cell lung cancer (NSCLC) samples from early stage lung cancer patients. In NSCLC biopsies, an immunocytochemical analysis showed cytoplasmic expression of CP-4 and CP-4a in normal lung bronchiolar epithelium. In contrast, CP-4 immunoreactivity was not found in 47% adenocarcinomas and 83% squamous cell carcinomas, whereas all of the tumors expressed CP-4a. Besides, lack of CP-4 expression was associated with high proliferation of the tumor (determined by Ki67 expression). By fluorescence in situ hybridization, >30% of NSCLC cell lines and tumors showed allelic losses at PCBP4, correlating with the absence of the protein. On the other hand, no mutations in the coding region of the gene were found in any of the 24 cell lines analyzed. By Northern blotting and real-time reverse transcription-PCR, we detected the expression of CP-4 and CP-4a messages in NSCLC and small cell lung cancer cell lines. Our data demonstrate an abnormal expression of CP-4 in lung cancer, possibly associated with an altered processing of the CP-4 mRNA leading to a predominant expression of CP-4a. This may be considered as an example of alternative splicing involved in tumor suppressor gene inactivation. Finally, induction of CP-4 expression reduced cell growth, in agreement with its proposed role as a tumor suppressor, and suggesting an association of this RNA-binding protein with lung carcinogenesis.

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