α7nAChR-mediated recruitment of PP1γ promotes TRAF6/NF-κB cascade to facilitate the progression of Hepatocellular Carcinoma

The cholinergic signaling pathways have been recently implicated in the development of various human cancers. However, the underlying molecular mechanism remains largely unclear. In the present study, we reported that 7 nicotinic acetylcholine receptor (7nAChR), an important member of nicotinic acetylcholine receptors, interacts with Protein Phosphatase-1 (PP1) in human Hepatocellular Carcinoma (HCC) tissues. In addition, we found that alpha nAChR facilitates the ubiquitination and activation of TRAF6 in a PP1-dependent manner in HCC cells. Furthermore, we showed that ligand-bounded alpha nAChR induces the degradation of IB, leading to resultant phosphorylation and nuclear accumulation of NF-kappa B p65. Accordingly, acetylcholine triggers the expression of critical NF-kappa B target genes, such as Cyclin D1 and PCNA, as well as the proliferation of HCC cells in a PP1- and alpha nAChR-dependent manner. Furthermore, we revealed that nicotine-triggered alpha nAChR activation promotes oncosphere formation and in vivo tumor growth of HCC cells. Moreover, we showed that the protein levels of both alpha nAChR and PP1 are significantly upregulated in human HCC specimens compared with adjacent non-cancerous ones, and that upregulated expression of the two proteins predict significantly worsened prognosis in HCC patients. These findings together indicate that the cholinergic receptor 7nAChR exerts a facilitating role in HCC development through PP1-dependent TRAF6/NF-kappa B signaling.