Role Of P73 Gene On The Biological Behavior Of Human Lung Cancer

Lung cancer has become the most common cause of cancer-related mortality in the world in both men and women. Despite the development of aggressive protocols utilizing chemotherapy, radiation therapy, and surgery, the overall survival of lung cancer has change little, with less than 15% of patients surviving long than five years. Molecular analysis has demonstrated that lung cancer cells accumulate a number of genetic alterations, including oncogenes and tumor suppressor genes, to develop an overt lung cancer. Because of these poor results and the recognition that cancer is caused by molecular defects, research has focused on developing novel therapeutics to try to correct these underlying genetic defects and reverse the malignant phenotype. Gene therapy is one such new therapeutic strategy.The tumor suppressor gene p53 is the most frequent target for gene alterations in human cancers, especially with lung cancer. Loss of p53 function occurs in up to 50% of non-small cell lung cancer and 70% small cell lung cancer. In many cases of neoplasia, cancer cells have evaded apoptosis despite severely mutated DNA because of p53 defects. Replacement of wtp53 by gene transfer techniques then allows restoration of the apoptotic process and destruction of the tumor cells. Replacement of the p53 gene has been shown to be effective in a clinical trial for patients with NSCLC. Combination of the p53 gene therapy and chemotherapy get better effect than either agent alone in clinical trial for patients with NSCLC. However, induction of apoptosis by the wtp53 protein has not been realized in all cases due to the resistance of some tumors to exogenous p53. To overcome these restrictions, genes that promote apoptosis by p53-independent mechanisms are particularly useful.The new identified p53 family member, p73, shows remarkable structural and functional similarity with p53 and thus generated instant expectations about analogous biological functions as tumor suppressor genes. Indeed, p73 is clearly involved in cancer, although in a distinct way to that of p53. However, despite its proapoptotic activity in vitro, the virtual absence of inactivating mutations, tumor-associated over expression of wtp73 in many different human cancers, and lack of a cancer phenotype in p73-null mice are inconsistentwith a classic suppressor function. How to explain the paradoxical behave of p73 gene?It is well known that p53 gene have not protein isoforms. Researchers presume mutation is the main mode of p53 gene function loss. In contrast to p53, p73 gene give rise to multiple functionally distinct protein isoforms due to alternative promoter utilization and alternative mRNA splicing. Furthermore the A N protein forms, which lack the N-terminal transactivation domain, can functions of the corresponding full-length proteins. Only further characterization of the full-length and N-terminal truncated forms of p73 will help to establish the cellular context in which p73 acts in a pro-apoptotic way as a tumor suppressor or in an anti-apoptotic potentially oncogenic manner. Further studies must assess the relation between p73 and its sibling p53 and whether p73 can became a new gene therapy target in lung cancer.It has been reported that two NSCLC cell lines H1299 (p53-null) and A549 (wtp53) with different genetic background possess different response to p53 gene therapy. The main purpose of this study was to explore the influence of wtp73 and ANp73 on the cell biological behavior and chemosensitivity of H1299 and A549 cells, analyzing the relationship of p73 and p53, to find the new lung cancer gene therapy target. The transcript expression of A Np73 was detected in 40 human NSCLC tissues and matched non-cancer lung tissues by semiquantitative RT-PCR.The conclusions of the study are as below:1. Exogenous wtp73 gene can inhibit proliferation and induce apoptosis of p53-sensitive and p53-resistant lung adenocarcionoma cell lines. The wtp73 antitumor activity was not affected by p53 gene status. p73 clearly have novel, p53-independent...