Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma
Abstract Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Serine‐arginine rich splicing factor 3 (SRSF3) plays a critical role in hepatocyte function and its loss in mice promotes chronic liver damage and leads to HCC. Hepatocyte‐specific SRSF3 knockout mice (SKO mice) also...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-07-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202105120 |
| _version_ | 1818177512089321472 |
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| author | Deepak Kumar Manasi Das Alexis Oberg Debashis Sahoo Panyisha Wu Consuelo Sauceda Lily Jih Lesley G. Ellies Magda T. Langiewicz Supriya Sen Nicholas J. G. Webster |
| author_facet | Deepak Kumar Manasi Das Alexis Oberg Debashis Sahoo Panyisha Wu Consuelo Sauceda Lily Jih Lesley G. Ellies Magda T. Langiewicz Supriya Sen Nicholas J. G. Webster |
| author_sort | Deepak Kumar |
| collection | DOAJ |
| description | Abstract Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Serine‐arginine rich splicing factor 3 (SRSF3) plays a critical role in hepatocyte function and its loss in mice promotes chronic liver damage and leads to HCC. Hepatocyte‐specific SRSF3 knockout mice (SKO mice) also overexpress insulin‐like growth factor 2 (IGF2). In the present study, double deletion of Igf2 and Srsf3 (DKO mice) prevents hepatic fibrosis and inflammation, and completely prevents tumor formation, and is associated with decreased proliferation, apoptosis and DNA damage, and restored DNA repair enzyme expression. This is confirmed in vitro, where IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage. Tumors from the SKO mice also show mutational signatures consistent with homologous recombination and mismatch repair defects. Analysis of frozen human samples shows that SRSF3 protein is decreased sixfold in HCC compared to normal liver tissue but SRSF3 mRNA is increased. Looking at public TCGA data, HCC patients having high SRSF3 mRNA expression show poor survival, as do patients with alterations in known SRSF3‐dependent splicing events. The results indicate that IGF2 overexpression in conjunction with reduced SRSF3 splicing activity could be a major cause of DNA damage and driver of liver cancer. |
| first_indexed | 2024-12-11T20:33:15Z |
| format | Article |
| id | doaj.art-62d5642666cc412fa26063b587ba6a76 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-11T20:33:15Z |
| publishDate | 2022-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-62d5642666cc412fa26063b587ba6a762022-12-22T00:51:45ZengWileyAdvanced Science2198-38442022-07-01921n/an/a10.1002/advs.202105120Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular CarcinomaDeepak Kumar0Manasi Das1Alexis Oberg2Debashis Sahoo3Panyisha Wu4Consuelo Sauceda5Lily Jih6Lesley G. Ellies7Magda T. Langiewicz8Supriya Sen9Nicholas J. G. Webster10Research and Development Service VA San Diego Healthcare System San Diego CA 92161 USADivision of Endocrinology and Metabolism, Department of Medicine University of California San Diego La Jolla CA 92093 USAResearch and Development Service VA San Diego Healthcare System San Diego CA 92161 USADivision of Genome Information Sciences, Department of Pediatrics University of California San Diego La Jolla CA 92093 USAResearch and Development Service VA San Diego Healthcare System San Diego CA 92161 USAResearch and Development Service VA San Diego Healthcare System San Diego CA 92161 USAResearch and Development Service VA San Diego Healthcare System San Diego CA 92161 USADivision of Cancer Biology Research, Department of Pathology University of California San Diego La Jolla CA 92093 USADivision of Endocrinology and Metabolism, Department of Medicine University of California San Diego La Jolla CA 92093 USADivision of Endocrinology and Metabolism, Department of Medicine University of California San Diego La Jolla CA 92093 USAResearch and Development Service VA San Diego Healthcare System San Diego CA 92161 USAAbstract Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Serine‐arginine rich splicing factor 3 (SRSF3) plays a critical role in hepatocyte function and its loss in mice promotes chronic liver damage and leads to HCC. Hepatocyte‐specific SRSF3 knockout mice (SKO mice) also overexpress insulin‐like growth factor 2 (IGF2). In the present study, double deletion of Igf2 and Srsf3 (DKO mice) prevents hepatic fibrosis and inflammation, and completely prevents tumor formation, and is associated with decreased proliferation, apoptosis and DNA damage, and restored DNA repair enzyme expression. This is confirmed in vitro, where IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage. Tumors from the SKO mice also show mutational signatures consistent with homologous recombination and mismatch repair defects. Analysis of frozen human samples shows that SRSF3 protein is decreased sixfold in HCC compared to normal liver tissue but SRSF3 mRNA is increased. Looking at public TCGA data, HCC patients having high SRSF3 mRNA expression show poor survival, as do patients with alterations in known SRSF3‐dependent splicing events. The results indicate that IGF2 overexpression in conjunction with reduced SRSF3 splicing activity could be a major cause of DNA damage and driver of liver cancer.https://doi.org/10.1002/advs.202105120insulin‐like growth factorliver cancerprognosisRNA splicing |
| spellingShingle | Deepak Kumar Manasi Das Alexis Oberg Debashis Sahoo Panyisha Wu Consuelo Sauceda Lily Jih Lesley G. Ellies Magda T. Langiewicz Supriya Sen Nicholas J. G. Webster Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma Advanced Science insulin‐like growth factor liver cancer prognosis RNA splicing |
| title | Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma |
| title_full | Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma |
| title_fullStr | Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma |
| title_full_unstemmed | Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma |
| title_short | Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma |
| title_sort | hepatocyte deletion of igf2 prevents dna damage and tumor formation in hepatocellular carcinoma |
| topic | insulin‐like growth factor liver cancer prognosis RNA splicing |
| url | https://doi.org/10.1002/advs.202105120 |
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