Nicotine Promotes WRL68 Cells Proliferation Due to the Mutant p53 Gain-of-Function by Activating CDK6-p53-RS-PIN1-STAT1 Signaling Pathway.

Abstract

The liver is an important organ with many tasks, such as dealing with drugs, alcohol and other toxins to remove them from the body. Nicotine is the more abundant component in cigarette smoking, which is first metabolized in liver and increases the risk of developing hepatocellular carcinoma (HCC). Also, genotoxic potential of nicotine has been extensively studied in vitro. However, the carcinogenic action of nicotine on the HCC needs to be elucidated. The current study demonstrated that chronic exposure to nicotine significantly promotes human normal fetal hepatic cell line (WRL68 cells) proliferation in a time- and concentration-dependent manner resulting from G0/G1-S-phase transition. Also remarkably, nicotine induced the level of p53 mutation at Ser249 (p53-RS). Note as well that the level of STAT1 protein was increased along with p53-RS owing to the prolonged half-life of STAT1. Furthermore, it is suggested that CDK6-dependent binding between phosphorylation of p53-RS at Ser249 and PIN1 by nicotine treatment leads to the nucleus translocation, followed by interacting with STAT1 and subsequent activation of STAT1 via the improvement of its stability, which is involved in cellular growth and colony formation after nicotine treatment. Simply put, these findings indicated that nicotine induces mutant p53 gain-of function (GOF), activating CDK6-p53-RS-PIN1-STAT1 signaling pathway and promoting cell proliferation, which could contribute to HCC for smokers.