{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Desert R"],"funding":["European Research Council","NIDDK NIH HHS","U.S. Department of Defense","NCI NIH HHS"],"pagination":["692-709"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8948552"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6(4)"],"pubmed_abstract":["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<sup>Hep</sup> transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (Opn<sup>ΔHep</sup> ) expressed a similar phenotype. The acute response to DEN was reduced in Opn<sup>ΔHep</sup> , which also showed more cancer stem/progenitor cells (CSCs, CD44<sup>+</sup> AFP<sup>+</sup> ) at 5 months. CSCs from Opn<sup>Hep</sup> Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from Opn<sup>Hep</sup> 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<sup>-/-</sup> compared with wild-type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44<sup>-/-</sup> Opn<sup>Hep</sup> 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."],"journal":["Hepatology communications"],"pubmed_title":["Role of Hepatocyte-Derived Osteopontin in Liver Carcinogenesis."],"pmcid":["PMC8948552"],"funding_grant_id":["R01 DK099558","671231","R01 CA233794","CA170172"],"pubmed_authors":["Desert R","Das S","Musso O","Nieto N","Athavale D","Abraham-Enachescu I","Ge X","Lantvit D","Chen W","Han H","Chen Y","Blajszczak C","Guzman G","Song Z","Hoshida Y"],"additional_accession":[]},"is_claimable":false,"name":"Role of Hepatocyte-Derived Osteopontin in Liver Carcinogenesis.","description":"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<sup>Hep</sup> transgenic [Tg]) showed increased tumor burden. Surprisingly, mice with conditional ablation of Opn in hepatocytes (Opn<sup>ΔHep</sup> ) expressed a similar phenotype. The acute response to DEN was reduced in Opn<sup>ΔHep</sup> , which also showed more cancer stem/progenitor cells (CSCs, CD44<sup>+</sup> AFP<sup>+</sup> ) at 5 months. CSCs from Opn<sup>Hep</sup> Tg mice expressed several mRNA signatures known to promote carcinogenesis, and mRNA signatures from Opn<sup>Hep</sup> 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<sup>-/-</sup> compared with wild-type mice. Finally, ablation of Cd44, an OPN receptor, did not reduce tumor burden in Cd44<sup>-/-</sup> Opn<sup>Hep</sup> 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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Apr","modification":"2025-05-18T12:07:33.766Z","creation":"2025-05-18T12:07:33.766Z"},"accession":"S-EPMC8948552","cross_references":{"pubmed":["34730871"],"doi":["10.1002/hep4.1845"]}}