title: Polo-like kinase 3 is associated with improved overall survival in cholangiocarcinoma.
abstract: OBJECTIVE
  Cholangiocarcinomas (CCA) paradoxically express the death ligand TRAIL and thus, are dependent on effective survival signals to circumvent apoptosis. Hedgehog signalling exerts major survival signals in CCA by regulating serine/threonine kinase polo-like kinase (PLK)2. We here aimed to examine the role of PLK1/2/3 expression for CCA tumour biology.
  
  
  METHODS
  We employed CCA samples from 73 patients and human HUCCT-1/Mz-CHA1/KMCH-1 CCA cells. Immunohistochemistry for PLK1/2/3 was performed using tissue microarrays from representative tumour areas.
  
  
  RESULTS
  PLK1/2/3-immunoreactive cancer cells were present in most of the CCA samples. However, only PLK1 and especially PLK3 were expressed in higher amounts within CCA cells as compared to normal liver. Given that fibroblast growth factor (FGF) can induce PLK3 expression and also is present in CCA, we examined the effect of FGF on PLK3 in vitro. Indeed, rhFGF rapidly increased PLK3 mRNA expression all three CCA cell lines giving an explanation for the abundant PLK3 presence in the tissue samples. Clinicopathologically, PLK3 expression was associated with decreased tumour cell migration and lymph/blood vessel infiltration whereas higher levels of PLK1 were correlated with larger tumour sizes. Moreover, strong PLK3 expression was associated with prolonged overall survival.
  
  
  CONCLUSIONS
  The results suggest that PLK3 predominantly is expressed in CCA cells and that high PLK3 expression correlates with prolonged overall survival. These observations might have implications for prognosis prediction of human CCA as well as the potential therapeutic use of polo-like kinase inhibitors (i.e., PLK1/2 specifity).
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Juntermanns
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Sydor
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
authors.forename: Gernot M
authors.initials: GM
authors.lastname: Kaiser
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
authors.forename: Derar
authors.initials: D
authors.lastname: Jaradat
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Joachim C
authors.initials: JC
authors.lastname: Mertens
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
authors.forename: Georgios C
authors.initials: GC
authors.lastname: Sotiropoulos
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Swoboda
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Neuhaus
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.affiliation: Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Mathé
authors.affiliation: Institute of Pathology, University Hospital Essen, Essen, Germany.
authors.forename: Hideo A
authors.initials: HA
authors.lastname: Baba
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Canbay
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Paul
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Fingas
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D001650:Bile Duct Neoplasms / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D000097868:Polo-like Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C486256:PLK3 protein, human; D000097868:Polo-like Kinases
keywords: apoptosis resistance; cell cycle enzymes; myofibroblasts; platelet-derived growth factor BB; tumour microenvironment