title: HuR Suppresses Fas Expression and Correlates with Patient Outcome in Liver Cancer.
abstract: Hepatocellular carcinomas (HCC) show resistance to chemotherapy and have blunt response to apoptotic stimuli. HCC cell lines express low levels of the Fas death receptor and are resistant to FasL stimulation, whereas immortalized hepatocytes are sensitive. The variable Fas transcript levels and consistently low Fas protein in HCC cells suggest posttranscriptional regulation of Fas expression. The 3'-untranslated region (UTR) of Fas mRNA was found to interact with the ribonucleoprotein Human Antigen R (HuR) to block mRNA translation. Silencing of HuR in HCC cells increased the levels of cell surface Fas and sensitized HCC cells to FasL. Two AU-rich domains within the 3'-UTR of Fas mRNA were identified as putative HuR-binding sites and were found to mediate the translational regulation in reporter assay. Hydrodynamic transfection of HuR plasmid into mice induced downregulation of Fas expression in livers and established functional resistance to the killing effects of Fas agonist. Human HCC tumor tissues showed significantly higher overall and cytoplasmic HuR staining compared with normal liver tissues, and the high HuR staining score correlated with worse survival of patients with early-stage HCC. Combined, the protumorigenic ribonucleoprotein HuR blocks the translation of Fas mRNA and effectively prevents Fas-mediated apoptosis in HCC, suggesting that targeting HuR would sensitize cells to apoptotic stimuli and reverse tumorigenic properties.
  
  
  CONCLUSIONS
  Demonstrating how death receptor signaling pathways are altered during progression of HCC will enable the development of better methods to restore this potent apoptosis mechanism.
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Haifeng
authors: H
authors: Zhu
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Zuzana
authors: Z
authors: Berkova
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Rohit
authors: R
authors: Mathur
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Lalit
authors: L
authors: Sehgal
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Tamer
authors: T
authors: Khashab
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Rong-Hua
authors: RH
authors: Tao
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Xue
authors: X
authors: Ao
authors: Department of Statistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Lei
authors: L
authors: Feng
authors: Baylor College of Medicine, Houston, Texas.
authors: Anita L
authors: AL
authors: Sabichi
authors: Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Boris
authors: B
authors: Blechacz
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Asif
authors: A
authors: Rashid
authors: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. fsamaniego@mdanderson.org.
authors: Felipe
authors: F
authors: Samaniego
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D000067780:ELAV-Like Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D019014:fas Receptor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D012333:RNA, Messenger; D019014:fas Receptor