Altered expression of splicing factor, heterogeneous nuclear ribonucleoprotein A2/B1, in mouse lung neoplasia

Our previous proteomic investigation of lung neoplasia in vitro demonstrated a high concentration of the lung cancer biomarker and splicing factor, hnRNP A2/B1, in the transformed mouse lung epithelial cell line, E9. Since changes in pre-mRNA splicing profoundly affect neoplastic progression, we examined hnRNP A2/B1 expression in chemically induced primary mouse lung tumors, an in vivo model of pulmonary adencocarcinoma. Tumor hnRNP A2/B1 content and spatial distribution assessed by immunohistochemistry varied with stage of progression, genetic background, and whether tumors were induced by a single agent (urethane) or by 2-stage initiation/promotion (3-methylcholanthrene/butylated hydroxytoluene) carcinogenesis. To address mechanisms governing hnRNP A2/B1 expression changes, we utilized in vitro models. hnRNP A2/B1 protein was overexpressed in E9, the spontaneous tranformant of immortalized but non-neoplastic E10 cells, but expression was not strictly a function of enhanced proliferative rate in neoplastic cells. Elevated mRNA contentwas positively associated with cell division in both E10 and E9, but hnRNP A2/B1 protein levels decreased in proliferating E10 cells. The increased mRNA reflected enhanced mRNA stability, as shown by measuring time-dependent mRNA decay after inhibiting transcription. Dysregulation of hnRNP A2/B1 expression during lung neoplasia in vivo thus depends on complex gene-environmental interactions that,affect cell type-specific changes in mRNA processing and, most probably, the rates of translation and/or protein degradation. (c) 2007 Wiley-Liss, Inc.