title: MACC1 suppresses cell apoptosis in hepatocellular carcinoma by targeting the HGF/c-MET/AKT pathway.
abstract: OBJECTIVE
  To investigate the expression and prognostic value of MACC1 in patients with HCC and identify the mechanism by which MACC1 inhibits HCC cell apoptosis.
  
  
  METHODS
  MACC1 and p-AKT expression was studied using immunohistochemistry of both HCC tissues and adjacent liver tissues. qRT-PCR and western immunoblotting were used to examine the expression of target genes at the mRNA and protein levels, respectively. The MTT assay was used to assess cell viability, and cell apoptosis was determined by DAPI staining, Annexin V/PI staining and Caspase 3/7 assay. Nude mice were used to perform in vivo experiments.
  
  
  RESULTS
  The overexpression of MACC1 was found in HCC tissues and was correlated with poor postsurgical prognosis. There was a positive relationship between MACC1 and p-AKT expression in HCC tissues. In vitro experiments showed that MACC1 repressed HCC cell apoptosis and promoted cell growth. Knockdown of c-MET abolished the anti-apoptotic function of MACC1. Next, MACC1 was verified to activate PI3K/AKT signaling by sensitizing HGF/c-MET signaling in HCC. MACC1 overexpression enhanced the HGF-driven phosphorylation of BAD, Caspase 9 and FKHRL1 and inhibited their pro-apoptotic functions in HCC cells. Finally, MACC1 was shown to inhibit cell apoptosis and promote HCC growth in vivo.
  
  
  CONCLUSIONS
  This investigation revealed that MACC1 overexpression predicted worse prognosis after liver resection, which was attributed to the repression of HCC cell apoptosis via a molecular mechanism in which MACC1 accelerated the activation of the HGF/c-MET/PI3K/AKT pathway and phosphorylated BAD, Caspase 9 and FKHRL1, ultimately preventing their nuclear translocation and their pro-apoptotic function.
authors: Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Yingmin
authors: Y
authors: Yao
authors: Chanwei
authors: C
authors: Dou
authors: Zhongtang
authors: Z
authors: Lu
authors: Xin
authors: X
authors: Zheng
authors: Qingguang
authors: Q
authors: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D051058:Oncogene Protein v-akt / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012333:RNA, Messenger; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D053453:Caspase 9; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017228:Hepatocyte Growth Factor; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C499517:FOXO3 protein, human; C066855:HGF protein, human; C544162:MACC1 protein, human