Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10
Abstract S100 proteins are significantly deregulated in hepatocellular carcinoma (HCC) and metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the impact of hepatocyte downregulation of two closely-related members of the S100 family, S100A10 and S100A11, in comple...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-08-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07940-2 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849225859386310656 |
|---|---|
| author | Etienne Delangre Marta Correia de Sousa Miranda Türkal Monika Gjorgjieva Suzanne Chartier Grégoire Arnoux Cyril Sobolewski Margot Fournier Christine Maeder Laura Rubbia-Brandt Pierre Maechler Michelangelo Foti |
| author_facet | Etienne Delangre Marta Correia de Sousa Miranda Türkal Monika Gjorgjieva Suzanne Chartier Grégoire Arnoux Cyril Sobolewski Margot Fournier Christine Maeder Laura Rubbia-Brandt Pierre Maechler Michelangelo Foti |
| author_sort | Etienne Delangre |
| collection | DOAJ |
| description | Abstract S100 proteins are significantly deregulated in hepatocellular carcinoma (HCC) and metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the impact of hepatocyte downregulation of two closely-related members of the S100 family, S100A10 and S100A11, in complementary mouse models of MASLD and liver cancer. Hepatotropic AAV8 encoding shRNAs targeting S100A10 or S100A11 were used to downregulate these proteins specifically in the liver of mice fed a diet inducing hepatic steatosis, inflammation, and fibrosis and in a genetic mouse model of MASLD bearing hepatocyte-specific deletion of PTEN (LPTENKO). The impact of S100A10 or S100A11 downregulation on liver tumor development was further investigated in aged LPTENKO mice spontaneously developing MASLD-driven HCC and in diethylnitrosamine (DEN)-injected mice fed or not with high fat diet. Finally, the upregulation and downregulations of S100A10 were performed in mice harbouring the over-expression of Myc and constitutively activated β-catenin, two main events occurring in a sub-type of human HCC. Downregulation of S100A10 promoted hepatocarcinogenesis in a fatty liver setting, while reducing steatosis and fibrosis development. S100A11 knock-down consistently reduced MASLD and tumoral growth. However, in vivo S100A11 downregulation triggered concomitant partial loss of endogenous protective S100A10. Overexpression of S100A10 reduced the volume of tumors and might represent a therapeutic option. The results show that both S100A10 and S100A11 play active roles in the development of MASLD. However, these two closely associated proteins present opposite contributions to hepatic cancer, S100A10 being protective and S100A11 deleterious. |
| format | Article |
| id | doaj-art-a6d617cc08d443efa38bc2ed6dbd9420 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-a6d617cc08d443efa38bc2ed6dbd94202025-08-24T11:54:25ZengNature Publishing GroupCell Death and Disease2041-48892025-08-0116111510.1038/s41419-025-07940-2Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10Etienne Delangre0Marta Correia de Sousa1Miranda Türkal2Monika Gjorgjieva3Suzanne Chartier4Grégoire Arnoux5Cyril Sobolewski6Margot Fournier7Christine Maeder8Laura Rubbia-Brandt9Pierre Maechler10Michelangelo Foti11Department of Cell Physiology and Metabolism, Faculty of Medicine, University of GenevaDepartment of Cell Physiology and Metabolism, Faculty of Medicine, University of GenevaDepartment of Cell Physiology and Metabolism, Faculty of Medicine, University of GenevaDepartment of Cell Physiology and Metabolism, Faculty of Medicine, University of GenevaService de Pathologie Clinique, Hôpitaux Universitaires de GenèveService de Pathologie Clinique, Hôpitaux Universitaires de GenèveDepartment of Cell Physiology and Metabolism, Faculty of Medicine, University of GenevaDepartment of Cell Physiology and Metabolism, Faculty of Medicine, University of GenevaDepartment of Cell Physiology and Metabolism, Faculty of Medicine, University of GenevaService de Pathologie Clinique, Hôpitaux Universitaires de GenèveDepartment of Cell Physiology and Metabolism, Faculty of Medicine, University of GenevaDepartment of Cell Physiology and Metabolism, Faculty of Medicine, University of GenevaAbstract S100 proteins are significantly deregulated in hepatocellular carcinoma (HCC) and metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we investigated the impact of hepatocyte downregulation of two closely-related members of the S100 family, S100A10 and S100A11, in complementary mouse models of MASLD and liver cancer. Hepatotropic AAV8 encoding shRNAs targeting S100A10 or S100A11 were used to downregulate these proteins specifically in the liver of mice fed a diet inducing hepatic steatosis, inflammation, and fibrosis and in a genetic mouse model of MASLD bearing hepatocyte-specific deletion of PTEN (LPTENKO). The impact of S100A10 or S100A11 downregulation on liver tumor development was further investigated in aged LPTENKO mice spontaneously developing MASLD-driven HCC and in diethylnitrosamine (DEN)-injected mice fed or not with high fat diet. Finally, the upregulation and downregulations of S100A10 were performed in mice harbouring the over-expression of Myc and constitutively activated β-catenin, two main events occurring in a sub-type of human HCC. Downregulation of S100A10 promoted hepatocarcinogenesis in a fatty liver setting, while reducing steatosis and fibrosis development. S100A11 knock-down consistently reduced MASLD and tumoral growth. However, in vivo S100A11 downregulation triggered concomitant partial loss of endogenous protective S100A10. Overexpression of S100A10 reduced the volume of tumors and might represent a therapeutic option. The results show that both S100A10 and S100A11 play active roles in the development of MASLD. However, these two closely associated proteins present opposite contributions to hepatic cancer, S100A10 being protective and S100A11 deleterious.https://doi.org/10.1038/s41419-025-07940-2 |
| spellingShingle | Etienne Delangre Marta Correia de Sousa Miranda Türkal Monika Gjorgjieva Suzanne Chartier Grégoire Arnoux Cyril Sobolewski Margot Fournier Christine Maeder Laura Rubbia-Brandt Pierre Maechler Michelangelo Foti Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10 Cell Death and Disease |
| title | Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10 |
| title_full | Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10 |
| title_fullStr | Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10 |
| title_full_unstemmed | Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10 |
| title_short | Comparative analysis of S100A10 and S100A11 in MASLD and hepatic cancer development revealed a tumor suppressive role for S100A10 |
| title_sort | comparative analysis of s100a10 and s100a11 in masld and hepatic cancer development revealed a tumor suppressive role for s100a10 |
| url | https://doi.org/10.1038/s41419-025-07940-2 |
| work_keys_str_mv | AT etiennedelangre comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT martacorreiadesousa comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT mirandaturkal comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT monikagjorgjieva comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT suzannechartier comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT gregoirearnoux comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT cyrilsobolewski comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT margotfournier comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT christinemaeder comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT laurarubbiabrandt comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT pierremaechler comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 AT michelangelofoti comparativeanalysisofs100a10ands100a11inmasldandhepaticcancerdevelopmentrevealedatumorsuppressiverolefors100a10 |