title: RARγ-induced E-cadherin downregulation promotes hepatocellular carcinoma invasion and metastasis.
abstract: Aberrant expression of Retinoic acid receptor γ (RARγ) is implicated in cancer development. Our previous study identified that RARγ functions as a tumor promoter to drive hepatocellular carcinoma (HCC) growth. However, its contribution to HCC invasion and metastasis remains unclear.
  
  
  
  RARγ expression in clinical HCC samples was detected by western blot and immunohistochemistry. The relationship between RARγ expression levels and the clinical characteristics were evaluated. HCC cell line MHCC-97H were stably knocked down RARγ using a lentivirus vector-based shRNA technique. The cells were analyzed by migration and invasion assays, and injected into nude mice to assess tumor metastasis. E-cadherin expression regulated by RARγ was examined by qPCR, western blot and immunofluorescence staining.
  
  
  
  The expression of RARγ is significantly upregulated in human HCC tissues. Moreover, its expression positively correlates with tumor size, distant metastasis and TNM stage, and negatively correlates with length of survival of HCC patients. Knockdown of RARγ markedly inhibits HCC cell invasion and metastasis both in vitro and in vivo. Mechanistic investigations reveal that RARγ functions through regulation of NF-κB-mediated E-cadherin downregulation to promote HCC invasion and metastasis. Notably, RARγ expression status negatively correlates with E-cadherin expression in HCC cell lines and clinical HCC samples.
  
  
  
  These findings demonstrate that RARγ could promote HCC invasion and metastasis by regulating E-cadherin reduction, and implicate new strategies to aggressively treat HCC through targeting RARγ/E-cadherin signaling axis.
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123, China.|The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Gan
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123, China.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Wang
authors.affiliation: The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Zhu
authors.affiliation: The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
authors.forename: Xiao-Shun
authors.initials: XS
authors.lastname: He
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123, China.
authors.forename: Peng-Da
authors.initials: PD
authors.lastname: Guo
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123, China.
authors.forename: Xiu-Ming
authors.initials: XM
authors.lastname: Li
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123, China. jianmingli@suda.edu.cn.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
authors.affiliation: Pathology Center and Department of Pathology, Soochow University, Suzhou, 215123, China. wuhua@suda.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D015854:Up-Regulation; D000097768:Retinoic Acid Receptor gamma
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D018168:Receptors, Retinoic Acid; D000097768:Retinoic Acid Receptor gamma; C513384:CDH1 protein, human
keywords: E-cadherin; Hepatocellular carcinoma; Metastasis; RARγ