Role of Hepatocyte-Derived Osteopontin in Liver Carcinogenesis.

Autor: Desert R; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Ge X; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Song Z; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Han H; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Lantvit D; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Chen W; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Das S; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Athavale D; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Abraham-Enachescu I; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Blajszczak C; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Chen Y; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Musso O; INSERM, University of Rennes, INRA, Institut NuMeCAN (Nutrition Metabolisms and Cancer), Rennes, France., Guzman G; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA., Hoshida Y; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA., Nieto N; Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA.; Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Jazyk: angličtina
Zdroj: Hepatology communications [Hepatol Commun] 2022 Apr; Vol. 6 (4), pp. 692-709. Date of Electronic Publication: 2021 Nov 03.
DOI: 10.1002/hep4.1845
Abstrakt: Osteopontin (OPN) expression correlates with tumor progression in many cancers, including hepatocellular carcinoma (HCC); however, its role in the onset of HCC remains unclear. We hypothesized that increased hepatocyte-derived OPN is a driver of hepatocarcinogenesis. Analysis of a tissue microarray of 366 human samples revealed a continuous increase in OPN expression during hepatocarcinogenesis. In patients with cirrhosis, a transcriptome-based OPN correlation network was associated with HCC incidence along 10 years of follow-up, together with messenger RNA (mRNA) signatures of carcinogenesis. After diethylnitrosamine (DEN) injection, mice with conditional overexpression of Opn in hepatocytes (Opn Hep transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (Opn ΔHep ) expressed a similar phenotype. The acute response to DEN was reduced in Opn ΔHep , which also showed more cancer stem/progenitor cells (CSCs, CD44 + AFP + ) at 5 months. CSCs from Opn Hep Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from Opn Hep Tg mice were associated with poor outcome in human HCC patients. Treatment with rOPN had little effect on CSCs, and their progression to HCC was similar in Opn -/- compared with wild-type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44 -/- Opn Hep Tg mice. Conclusions: Hepatocyte-derived OPN acts as a tumor suppressor at physiological levels by controlling the acute response to DEN and the presence of CSCs, while induction of OPN is pro-tumorigenic. This is primarily due to intracellular events rather that by the secretion of the protein and receptor activation.
(© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
Externí odkaz: