title: Stearoyl-CoA desaturase plays an important role in proliferation and chemoresistance in human hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is often diagnosed at an advanced stage, when it is not amenable for aggressive therapies such as surgical resection or liver transplantation. Current therapeutic options achieve clinical responses in only a small percentage of cases. As a consequence, effective approaches for prevention and treatment are greatly needed. Altered lipid metabolism has been recently linked to HCC pathogenesis. The aims of this study were to define the cellular and molecular mechanisms linking stearoyl-CoA desaturase (SCD), the rate-limiting enzyme and an essential regulator of lipid homeostasis in liver cells, to carcinogenesis in HCC.
  
  
  METHODS
  HCC and normal liver specimens were collected. Human HCC cell lines: HepG2, Hep3B, and PLC/PLF/5 were used for immunoblot, cell viability, proliferation, and apoptosis assays. Small interfering RNAs were used for genetic inhibition, and 10, 12 conjugated linoleic acid was used for pharmacologic SCD inhibition.
  
  
  RESULTS
  SCD was strongly expressed in surgically resected HCC (n = 64) and various human HCC cell lines (HepG2, Hep3B, and PLC/PLF/5). The levels of SCD negatively correlated with degree of tumor differentiation (P < 0.01). Treatment of these HCC cell lines with a panel of chemotherapeutic drugs resulted in a time-dependent, phosphatidylinositol 3 kinase- and c-Jun N-terminal kinases1/2-mediated upregulation of SCD expression, which paralleled the degree of resistance to drug-induced apoptosis. Specific genetic or pharmacologic SCD suppression resulted in inhibition of cell proliferation (P < 0.001) and significantly increased sensitivity to chemotherapy-induced apoptosis.
  
  
  CONCLUSIONS
  Our data suggest that increased SCD expression plays an important role in HCC development and resistance to chemotherapy-induced apoptosis, and this is in part mediated by phosphatidylinositol 3 kinase/c-Jun N-terminal kinases activation. Specific targeted interruption of this pathway in HCC could be a desirable approach in designing novel therapeutic strategies.
authors.affiliation: Department of Pediatric Surgery, Children's Hospital Colorado, Aurora, Colorado. Electronic address: foldervip@yahoo.com.
authors.forename: Samiksha
authors.initials: S
authors.lastname: Bansal
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.forename: Naim
authors.initials: N
authors.lastname: Alkhouri
authors.forename: David A
authors.initials: DA
authors.lastname: Partrick
authors.forename: John J
authors.initials: JJ
authors.lastname: Fung
authors.forename: Ariel
authors.initials: A
authors.lastname: Feldstein
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D056945:Hep G2 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D013230:Stearoyl-CoA Desaturase / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology
chemical_list: C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D013230:Stearoyl-CoA Desaturase; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Apoptosis; Carcinogenesis; Chemotherapy; Lipid metabolism; Stearoyl-CoA desaturase