title: Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. While sorafenib, a multikinase inhibitor targeting the Raf/extracellular signal-regulated protein kinase (ERK) pathway, has been shown recently to provide a survival advantage to patients with advanced HCC, a predictive biomarker has not been developed. We studied whether c-Jun N-terminal kinase (JNK), which promotes liver carcinogenesis in mice, affects therapeutic response to sorafenib in HCC patients.
  
  
  METHODS
  We collected pathological specimens from 39 patients with advanced HCC before starting sorafenib treatment, and measured JNK activity in HCCs.
  
  
  RESULTS
  In patients treated with sorafenib, the expression of phospho-c-Jun in HCC, as a read out of JNK activity, was significantly higher (P<0.001) in the non-responder group than in the responder group. c-Jun N-terminal kinase activation in HCC was associated with a decreased time to progression and a poor overall survival (P=0.0028 and P=0.0008, respectively).
  
  
  CONCLUSIONS
  In addition, JNK activity was significantly correlated with CD133 expression level. Correspondingly, high expression level of CD133 was linked to a poor response to sorafenib. Furthermore, D-JNKi, a specific JNK inhibitor, reduced the growth of xenografted CD133(+) cells in athymic mice. In conclusion, JNK activation was positively correlated with CD133 expression level and inversely correlated with the therapeutic response to sorafenib, suggesting that JNK activity may be considered as a new predictive biomarker for response to sorafenib treatment.
authors.affiliation: Department of Gastroenterology and Hepatology, Kinki University, Osaka-Sayama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hagiwara
authors.forename: M
authors.initials: M
authors.lastname: Kudo
authors.forename: T
authors.initials: T
authors.lastname: Nagai
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: K
authors.initials: K
authors.lastname: Ueshima
authors.forename: N
authors.initials: N
authors.lastname: Nishida
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Sakurai
mesh_terms: D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009536:Niacinamide / Q000031:analogs & derivatives; D010455:Peptides / Q000378:metabolism*; D010671:Phenylurea Compounds; D011379:Prognosis; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D015533:Transcriptional Activation; D016896:Treatment Outcome
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D001557:Benzenesulfonates; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; D010671:Phenylurea Compounds; C000606024:Prom1 protein, mouse; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D048031:JNK Mitogen-Activated Protein Kinases