title: Acetylcholinesterase, a key prognostic predictor for hepatocellular carcinoma, suppresses cell growth and induces chemosensitization.
abstract: Acetylcholinesterase (ACHE) plays important roles in the cholinergic system, and its dysregulation is involved in a variety of human diseases. However, the roles and implications of ACHE in hepatocellular carcinoma (HCC) remain elusive. Here we demonstrate that ACHE was significantly down-regulated in the cancerous tissues of 69.2% of HCC patients, and the low ACHE expression in HCC was correlated with tumor aggressiveness, an elevated risk of postoperative recurrence, and a low survival rate. Both the recombinant ACHE protein and the enhanced expression of ACHE significantly inhibited HCC cell growth in vitro and tumorigenicity in vivo. Further study showed that ACHE suppressed cell proliferation via its enzymatic activity of acetylcholine catalysis and degradation. Moreover, ACHE could inactivate mitogen-activated protein kinase and phosphatidyl inositol-3'-phosphate kinase/protein kinase B pathways in HCC cells and thereby increase the activation of glycogen synthase kinase 3β and lead to β-catenin degradation and cyclin D1 suppression. In addition, increased ACHE expression could remarkably sensitize HCC cells to chemotherapeutic drugs (i.e., adriamycin and etoposide).
  
  
  CONCLUSIONS
  For the first time, we describe the function of ACHE as a tumor growth suppressor in regulating cell proliferation, the relevant signaling pathways, and the drug sensitivity of HCC cells. ACHE is a promising independent prognostic predictor for HCC recurrence and the survival of HCC patients. These findings provide new insights into potential strategies for drug discovery and improved HCC treatment.
authors.affiliation: Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.forename: Xin
authors.initials: X
authors.lastname: Hui
authors.forename: Mingxia
authors.initials: M
authors.lastname: Yan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gao
authors.forename: Taoyang
authors.initials: T
authors.lastname: Chen
authors.forename: Jinjun
authors.initials: J
authors.lastname: Li
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Dafang
authors.initials: D
authors.lastname: Wan
authors.forename: Jianren
authors.initials: J
authors.lastname: Gu
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
authors.forename: Xianghuo
authors.initials: X
authors.lastname: He
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D005047:Etoposide; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D000110:Acetylcholinesterase