Cellular and Molecular Mechanisms of Nicotine and Nitrosamines Promote Tumorigenic Behaviors in Renal Cell Carcinoma (II)

Renal cell carcinoma (RCC) is a molecularly heterogeneous disease that is refractory to standard conventional therapies. Over 25% of patients have presented metastasis when they are diagnosed. Once metastatic RCC occurs, it represented with poor 5-year survival rate. Although cigarette smoking is considered a causal risk factor for RCC, but the mechanisms associated with smoking and RCC carcinogenesis still remain largely unclear. Among thousands of chemicals in tobacco smoke, polycyclic aromatic hydrocarbons and nicotine-derived nitrosamines have been identified as the potent carcinogens in certain types of cancer initiation by forming DNA adducts, and cause mutation in vital genes like Rb, p53, and K-Ras. While these genes make only a small contribution to RCC, other genetic and epigenetic mechanisms may be also involved. Recent evidences have presented that nicotine and nitrosamines can also contribute to certain epigenetic mechanisms in lung, breast, colon and gastric cancers through nicotinic acetylcholine receptors (nAChRs) in promoting tumorigenic behaviors such as proliferation, migration, invasion and metastasis. In our ongoing study, we had found that transformed human renal tubular cell line, HK-2 had only expressed the mRNA of nicotinic acetylcholine receptors (nAChRs) a5, a7, a10, pi and P4. Among these, the RCC cell line ACHN cell was increased the mRNA expression levels of nAChR a5, a7, a10 and pi in compare to HK-2 cell. Form the immunohistochemical analysis with two different sets of commercialized RCC tissue arrays, the up-regulation of nAChR a7 was associated with the grade of ccRCC, while nAChR pi had less changed. In addition, treatment of nicotine and nitrosamines can increase the metastatic abilities of RCC cell lines ACHN and A498, including enhanced chemotactic motility; accelerated the cell migration and mediated VEGF secretion, but not in the cell growth. The migratory potential may relate to the mechanisms of epithelial mesenchymal transition, STAT3 phosphorylation, GTPase RhoA/Rac 1/Cdc42 activation and angiogenesis. In the current proposal, we will further delineate the above-mentioned molecular mechanisms in regulating nicotine and nitrosamines mediated RCC cell metastasis in vitro and in a tumor xenograft model. This study may provide new information of molecular pathogenesis of RCC and lead to new research direction on RCC therapy.