title: Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism.
abstract: OBJECTIVE
  Cholangiocarcinoma is a devastating cancer of biliary origin with limited treatment options. The growth factor, progranulin, is overexpressed in a number of tumours. The study aims were to assess the expression of progranulin in cholangiocarcinoma and to determine its effects on tumour growth.
  
  
  METHODS
  The expression and secretion of progranulin were evaluated in multiple cholangiocarcinoma cell lines and in clinical samples from patients with cholangiocarcinoma. The role of interleukin 6 (IL-6)-mediated signalling in the expression of progranulin was assessed using a combination of specific inhibitors and shRNA knockdown techniques. The effect of progranulin on proliferation and Akt activation and subsequent effects of FOXO1 phosphorylation were assessed in vitro. Progranulin knockdown cell lines were established, and the effects on cholangiocarcinoma growth were determined.
  
  
  RESULTS
  Progranulin expression and secretion were upregulated in cholangiocarcinoma cell lines and tissue, which were in part via IL-6-mediated activation of the ERK1/2/RSK1/C/EBPβ pathway. Blocking any of these signalling molecules, by either pharmacological inhibitors or shRNA, prevented the IL-6-dependent activation of progranulin expression. Treatment of cholangiocarcinoma cells with recombinant progranulin increased cell proliferation in vitro by a mechanism involving Akt phosphorylation leading to phosphorylation and nuclear extrusion of FOXO1. Knockdown of progranulin expression in cholangiocarcinoma cells decreased the expression of proliferating cellular nuclear antigen, a marker of proliferative capacity, and slowed tumour growth in vivo.
  
  
  CONCLUSIONS
  Evidence is presented for a role for progranulin as a novel growth factor regulating cholangiocarcinoma growth. Specific targeting of progranulin may represent an alternative for the development of therapeutic strategies.
authors: Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, TX 76504, USA.
authors: Gabriel
authors: G
authors: Frampton
authors: Pietro
authors: P
authors: Invernizzi
authors: Francesca
authors: F
authors: Bernuzzi
authors: Hae Yong
authors: HY
authors: Pae
authors: Matthew
authors: M
authors: Quinn
authors: Darijana
authors: D
authors: Horvat
authors: Cheryl
authors: C
authors: Galindo
authors: Li
authors: L
authors: Huang
authors: Matthew
authors: M
authors: McMillin
authors: Brandon
authors: B
authors: Cooper
authors: Lorenza
authors: L
authors: Rimassa
authors: Sharon
authors: S
authors: DeMorrow
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000473:pathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000077153:Progranulins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D000077153:Progranulins; D051057:Proto-Oncogene Proteins c-akt