title: The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma.
abstract: OBJECTIVE
  The correlation of the hedgehog signaling pathway with the progression, prognosis, and therapeutics of intrahepatic cholangiocellular carcinoma (ICC) has not been well documented. The study aimed to investigate the expression, prognostic significance, and therapeutic value of hedgehog components in ICC.
  
  
  METHODS
  Two independent cohorts of 200 patients with ICC were enrolled. By real-time PCR and immunohistochemistry assay, hedgehog components expression was evaluated. The prognostic values of hedgehog proteins were identified and verified. Cyclopamine or siRNA-targeting Gli was used to block the hedgehog signaling. Cell proliferation and apoptosis were observed by CCK8, cell cycle, and annexin V staining assays. In vivo murine tumor model was used to evaluate the role of hedgehog in ICC.
  
  
  RESULTS
  In ICC tissues, the Gli1 nuclear immune-intensity was associated with intrahepatic metastasis and the expression of Gli2 was associated with intrahepatic metastasis, venous invasion, and Unio Internationale Contra Cancrum (UICC) pT characteristics. In survival analysis, high Gli1 or Gli2 expressers had an unfavorable overall survival (OS) prognosis and a shorter disease-free survival (DFS) than those with low expression. In multivariate analysis, Gli1 expression was found to be an independent prognostic factor of OS, which was validated by another independent cohort. Furthermore, blocking the hedgehog signaling by cyclopamine or siRNA-targeting Gli1 resulted in apoptosis and growth inhibition in ICC cells.
  
  
  CONCLUSIONS
  This study shows, for the first time, activation of hedgehog pathway associated with the progression and metastasis in ICC, which may provide prognostic and therapeutic values for this tumor.
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tang
authors.forename: Ye-Xiong
authors.initials: YX
authors.lastname: Tan
authors.forename: Bei-Ge
authors.initials: BG
authors.lastname: Jiang
authors.forename: Yu-Fei
authors.initials: YF
authors.lastname: Pan
authors.forename: Shuang-Xi
authors.initials: SX
authors.lastname: Li
authors.forename: Guang-Zhen
authors.initials: GZ
authors.lastname: Yang
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Zhou
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Dong
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D001653:Bile Ducts, Intrahepatic; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D011379:Prognosis; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014704:Veratrum Alkaloids / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: C400551:GLI1 protein, human; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D014157:Transcription Factors; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; C000541:cyclopamine