Strong Down-Regulation of Tumor Suppressor Genes RB1 and CTDSPL is Associated with Aberrant Expression of Cell Cycle Regulation Genes in Non-Small Cell Lung Cancer

The search of specific molecular markers for differential diagnostics and new targets for combined targeted therapy or gene therapy is one of the key goals of molecular oncology. The first step in this direction is a comparative expression analysis of genes involved in a complex network of interactions of cell cycle control molecules in tumors. In the present study, advanced quantitative expression analysis of 84 genes (Human Cell Cycle Regulation Panel, Roche) revealed dysfunctions of p16INK4A?Cdk/cyclin D1?Rb and p53/ p21Waf1 pathways associated with strong down-regulation of two tumorsuppressor genes, RB1 and CTDSPL, in non-small cell lung cancer (NSCLC). Rb protein, a key regulator of cell cycle, can be activated by small CTD-serine phosphatase CTDSPL/RBSP3. The analysis revealed that over-expression of many genes from the panel was stronger in lung adenocarcinoma (ADC) than squamous cell carcinoma (SCC) and more pronounced in metastatic tumors. A number of genes showed expression alterations which were specific to NSCLC histological type or metastases presence. These genes could be potential NSCLC biomarkers. Twenty five genes (survivin, cyclins, Ser/Thrprotein kinases, transcription factors, phosphatases, etc.) with the strongest expression gains (up to 100-fold) could be potential targets for future biotherapy approach of NSCLC (both ADC and SCC). Our data concerning incremental deregulation of RB1, CTDSPL and other cell cycle control genes are in flow with the continuum model for tumor suppression.