The role of β2-AR/PI3K/AKT pathway in the proliferation, migration and invasion of THLE-2 cells induced by nicotine

Abstract

Nicotine, the primary constituent of tobacco, is one of the important factors that induce the occurrence of hepatocellular carcinoma (HCC). The β2-adrenergic receptor (β2-AR) is implicated in the growth and advancement of tumors. However, the role of β2-AR and its mediated cascades in nicotine-induced HCC remains unclear. This present study aims to observe the effects of nicotine on the proliferation, migration, and invasion of immortalized human liver epithelial (THLE-2) cells, as well as to explore the underlying mechanisms of action. The results of cell counting kit-8 (CCK-8) assay showed that 0.3125 μM nicotine had the ability to promote the proliferation of THLE-2 cells with a significant time-dependent manner. Therefore, THLE-2 cells were mainly selected for chronic treatment with 0.3125 μM nicotine in the later stage to cause transformation. After 30 passages of THLE-2 cells with 0.3125 μM nicotine treatment, chronic exposure to nicotine significantly enhanced the proliferation, metastasis, and invasion of cells. Besides, it also upregulated the intracellular levels of β2-AR, phosphoinositide 3-kinase (PI3K), AKT, matrix metalloproteinase-2 (MMP-2) and Cyclin D1, as well as downregulated the expression of p53. More importantly, the β2-AR/PI3K/AKT pathway was found to mediate the expression of MMP-2, Cyclin D1, and p53 in THLE-2 cells, playing a crucial role in their proliferation, migration, and invasion after continuous exposure to nicotine. Simply put, it demonstrated the role of β2-AR/PI3K/AKT pathway in the transformation of THLE-2 cells induced by nicotine. This study could provide valuable insights into the relationship between nicotine and HCC. Additionally, it lays the groundwork for investigating potential anticancer treatments for liver cancer linked to tobacco consumption.