The Study On The Function And The Molecular Mechanism Of Acetylcholinesterase In Hepatic Carcinogenesis

In recent years, cancer has been known to be a systemic disease with a large variety of deviations of oncogenes and tumor-suppressor genes. Liver cancer, including hepatocellular carcinoma (HCC) and hepatoblastoma, is one of the most prevalent and lethal cancers in China. Recent studies revealed that the pathogenesis and development of HCC is involved in a large variety of dysregulations of signaling pathways and deviations of oncogenes and/or tumor suppressor genes. Our previous study of a large-scale complementary DNA transfection screening showed that some cytokines or receptors driven from neural system are related to the proliferation of hepatocellular carcinoma cells. In the present study, we investigated the existence and function of the cholinergic system in hepatic cancer cells and identified the down-regulation of its key component acetylcholinesterase (ACHE), and further explored its function and the molecular mechanism of ACHE in hepatic cancer cells.ACHE plays important roles in the cholinergic system, and its dysregulation involves in a variety of human diseases. However, the roles and implications of ACHE in hepatic cancer remain elusive. Here, we demonstrated that the cholinergic system exists in hepatic cancer cells. Importantly, ACHE is significantly down-regulated in HCC tissues. Both the recombinant ACHE protein and the over-expression of ACHE by lenti-virus obviously inhibit the cell proliferation rate, the colony formation ability in vitro as well as tumor formation capability in vivo. Further study showed that Ach enhances HCC cell proliferation and ACHE suppresses cell proliferation via its enzymatic activity of catalyzing and degrading acetylcholine (Ach). Moreover, ACHE could inactivate mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways in HCC cells; and it could obviously increase the activation of glycogen synthase kinase 3β(GSK3β), thus resulting in P-catenin degradation and cyclin D1 suppression. In addition, the recombinant ACHE protein or the increase of ACHE expression could remarkably enhanced the drug-induced apoptosis in hepatic cancer cells and sensitize these cells to chemotherapeutical drugs, i.e. Adriamycin and Etoposide.In conclusion, we have for the first time demonstrated that the cholinergic system exists in HCC and ACHE functions as a tumor growth suppressor in regulating cell proliferation, the relevant signaling pathways and the drug sensitivity of HCC cells. These findings provide new insights into the potential strategy for the treatment of HCC.Abbreviations:Ach, acetylcholine; ACHE, acetylcholinesterase; AD, Alzheimer's disease; ADR, adriamycin; Carbachol, Carbamoylcholine; AFB, Aflatoxin B; CHAT, choline acetyltransferase; CNL, the corresponding noncancerous liver; EGF, Epidermal Growth Factor; ERK, extracellular signal-regulated kinase; GSK3β, glycogen synthase kinase 3β; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LiCl, Lithium chloride; mAChR, muscarinic-acetylcholine receptor; MAPK, mitogen-activated protein kinase; MEC, Mecamylamine; MEK, mitogen-activated protein kinase kinase; nAChR, nicotinyl-acetylcholine receptor; Neo, Neostigmine; PCR, polymerase chain reaction; PI3K, phosphatidyl inositol-3'-phosphate-kinase; VAChT, the vesicular Acetylcholine transporter; VP-16, etoposide; Wm, Wortmannin.