title: RhoE is frequently down-regulated in hepatocellular carcinoma (HCC) and suppresses HCC invasion through antagonizing the Rho/Rho-kinase/myosin phosphatase target pathway.
abstract: Deregulation of Rho guanosine triphosphatase (GTPase) pathways plays an important role in tumorigenesis and metastasis of hepatocellular carcinoma (HCC). RhoE/Rnd3 belongs to an atypical subfamily of the RhoGTPase, the Rnd family, as it lacks the intrinsic GTPase activity and remains always in its active GTP-bound form. In this study we investigated the role of RhoE in HCC. We examined the expression of RhoE in primary HCC samples from patients predominantly infected with the hepatitis B virus (HBV) and found that the RhoE messenger RNA (mRNA) level was frequently down-regulated (83.1%, 59/71) in HCCs. Low expression of RhoE in the tumors was significantly associated with shorter disease-free survival (P = 0.020) of the patients. Knockdown of RhoE by short-hairpin RNA using a lentiviral approach led to increased cell motility and invasiveness in SMMC7721 and BEL7402 HCC cells. Moreover, in vivo an orthotopic liver injection model in nude mice further demonstrated that knockdown of RhoE enhanced local invasion of HCC cells in the livers, with more invasive tumor front and increased incidence of venous invasion. Mechanistically, stable knockdown of RhoE in HCC cells significantly enhanced the phosphorylation of myosin phosphatase, promoted assembly of stress fibers, and increased the formation of plasma membrane blebbings, all these changes and activities being associated with activation of the Rho/Rho-kinase (ROCK) pathway.
  
  
  CONCLUSIONS
  RhoE was frequently down-regulated in predominantly HBV-associated HCCs and this down-regulation was associated with a more aggressive HCC phenotype. RhoE regulated the cytoskeleton remodeling and suppressed HCC motility and invasiveness by way of inhibiting the Rho/ROCK axis.
authors: State Key Laboratory for Liver Research, University of Hong Kong, Hong Kong.
authors: Wei
authors: W
authors: Ma
authors: Carmen Chak-Lui
authors: CC
authors: Wong
authors: Edmund Kwok-Kwan
authors: EK
authors: Tung
authors: Chun Ming
authors: CM
authors: Wong
authors: Irene Oi-Lin
authors: IO
authors: Ng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000502:physiology; D002465:Cell Movement; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D015398:Signal Transduction; D022502:Stress Fibers / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins