Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism
| Autor: | Sharon DeMorrow, Brandon Cooper, Lorenza Rimassa, Cheryl Galindo, Darijana Horvat, Li Huang, Matthew A. Quinn, Matthew McMillin, Gabriel Frampton, Hae Yong Pae, Francesca Bernuzzi, Pietro Invernizzi |
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| Přispěvatelé: | Frampton, G, Invernizzi, P, Bernuzzi, F, Pae, H, Quinn, M, Horvat, D, Galindo, C, Huang, L, Mcmillin, M, Cooper, B, Rimassa, L, Demorrow, S |
| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Immunoblotting FOXO1 Biology Real-Time Polymerase Chain Reaction digestive system Cholangiocarcinoma Small hairpin RNA Mice Progranulins Downregulation and upregulation MED/12 - GASTROENTEROLOGIA Cell Line Tumor Internal medicine mental disorders Intercellular Signaling Peptides and Protein Biomarkers Tumor medicine Animals Humans Bile Duct Neoplasm Protein kinase B Cell Proliferation Mice Inbred BALB C Gene knockdown Animal Forkhead Box Protein O1 Interleukin-6 Cell growth Growth factor Gastroenterology Forkhead Transcription Factors Forkhead Transcription Factor digestive system diseases Bile Ducts Intrahepatic Endocrinology Bile Duct Neoplasms Tissue Array Analysis Cancer research Intercellular Signaling Peptides and Proteins Signal transduction Tissue Array Analysi Proto-Oncogene Proteins c-akt Human Signal Transduction |
| Zdroj: | Gut. 61:268-277 |
| ISSN: | 1468-3288 0017-5749 |
| DOI: | 10.1136/gutjnl-2011-300643 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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