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Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism
  1. Gabriel Frampton1,2,
  2. Pietro Invernizzi3,
  3. Francesca Bernuzzi3,4,
  4. Hae Yong Pae1,2,
  5. Matthew Quinn1,2,
  6. Darijana Horvat1,2,
  7. Cheryl Galindo1,2,
  8. Li Huang5,
  9. Matthew McMillin1,2,
  10. Brandon Cooper6,
  11. Lorenza Rimassa7,
  12. Sharon DeMorrow1,2,8
  1. 1Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Temple, Texas, USA
  2. 2Department of Internal Medicine, Digestive Disease Research Center, Scott & White Hospital, Temple, Texas, USA
  3. 3Center for Autoimmune Liver Diseases, Division of Internal Medicine, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
  4. 4Department of Translational Medicine, Università degli studi di Milano, Rozzano, Italy
  5. 5Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
  6. 6Southwestern University, Georgetown, Texas, USA
  7. 7UO Oncologia medica e ematologia, Humanitas Cancer Center, IRCCS Istituto Clinico Humanitas, Rozzano, Italy
  8. 8Research Service, Central Texas Veterans Health Care System, Temple, Texas USA
  1. Correspondence to Sharon DeMorrow, Department of Internal Medicine, Scott and White Hospital and Texas A&M Health Science Center, Central Texas Veterans Health Care System, Building 205, 1901 S 1st St Temple, TX 76504, USA; demorrow{at}


Background and objectives 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.

  • IL-6
  • C/EBPβ
  • FOXO1
  • growth factors
  • biliary cancer
  • autoimmunity
  • primary biliary cirrhosis
  • autoimmune biliary disease
  • primary sclerosing cholangitis
  • cholangiocarcinoma
  • abdominal surgery
  • acute pancreatitis
  • bile duct surgery
  • acute liver failure
  • bile acid metabolism
  • cholangiocarcinoma
  • biliary physiology
  • biliary epithelium
  • molecular biology
  • bile acid

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  • See Commentary, p 170

  • Funding This work was supported by an NIH K01 grant award (DK078532) and an NIH R03 grant award (DK088012) to SD. FB was in part supported by Clonit s.r.l., Milan, Italy. This material is the result of work supported with resources of, and use of facilities at, the Central Texas Veterans Health Care System, Temple, Texas.

  • Competing interests None.

  • Ethics approval The ethics committee of the IRCCS Istituto Clinico Humanitas.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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