title: A20 suppresses hepatocellular carcinoma proliferation and metastasis through inhibition of Twist1 expression.
abstract: BACKGROUND
  Aberrant expression of A20 has been reported in several human malignancies including hepatocellular carcinoma (HCC). However, its clinical relevance and potential role in HCC remain unknown.
  
  
  METHODS
  Quantitative PCR, Western blots and immunohistochemistry analyses were used to quantify A20 expression in HCC samples and cell lines. The correlation of A20 expression with clinicopathologic features was analyzed in a cohort containing 143 patients with primary HCC. Kaplan-Meier curves were used to evaluate the association between A20 expression and patient survival. Functional studies were performed to determine the effects of A20 on proliferation and metastasis of HCC cells in vitro and in vivo.
  
  
  RESULTS
  Expression of A20 was increased in HCC tissues and cell lines. Increased expression of A20 was negatively correlated with the tumor size, TNM stage, tumor thrombus formation, capsular invasion and serum AFP levels. Patients with higher A20 expression had a prolonged disease-free survival and overall survival than those with lower A20 expression. Forced expression of A20 significantly inhibited the proliferative and invasive properties of HCC cells both in vitro and in vivo, whereas knockdown of A20 expression showed the opposite effects. Further studies revealed that expression of A20 was inversely correlated with Twist1 levels and NF-κB activity in HCC tissues and cell lines. A20-induced suppression of proliferation and migration of HCC cells were mainly mediated through inhibition of Twist1 expression that was regulated at least partly by A20-induced attenuation of NF-κB activity.
  
  
  CONCLUSIONS
  Our results demonstrate that A20 plays a negative role in the development and progression of HCC probably through inhibiting Twist1 expression. A20 may serve as a novel prognostic biomarker and potential therapeutic target for HCC patients.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. chenocean@163.com.|Anal-Colorectal Surgery Institute, 150th Hospital of PLA, Luoyang, China. chenocean@163.com.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Anal-Colorectal Surgery Institute, 150th Hospital of PLA, Luoyang, China. lianghudoc@163.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. luozaili111@163.com.
authors.forename: Zaili
authors.initials: Z
authors.lastname: Luo
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. zhang_jian032@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. zhangcunzhen87@163.com.
authors.forename: Cunzhen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. qiubijun1984@163.com.
authors.forename: Bijun
authors.initials: B
authors.lastname: Qiu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. liweidongdlw@163.com.
authors.forename: Liwei
authors.initials: L
authors.lastname: Dong
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. yxtan1214@163.com.
authors.forename: Yexiong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. dingjindj2015@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Ding
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. tangshanhua001@163.com.
authors.forename: Shanhua
authors.initials: S
authors.lastname: Tang
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. shenfengehbh@sina.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Shen
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. lizhongsh@yahoo.com.|Shanghai Institute of Cell Therapy Research, Shanghai, China. lizhongsh@yahoo.com.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute/Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China. hywangk@vip.sina.com.|National Center for Liver Cancer, Shanghai, China. hywangk@vip.sina.com.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3