ARMCX3 Mediates Susceptibility to Hepatic Tumorigenesis Promoted by Dietary Lipotoxicity
| Autor: | José María Balibrea, Roman Serrat, Carmen Berasain, Monica Higuera, Aleix Gavaldà-Navarro, Eduardo Soriano, Matías A. Avila, Iker Uriarte, María Teresa Salcedo, Francesc Villarroya, Eva Santamaría, Beatriz Minguez, Yasmina Manso, Serena Mirra, Ferran Burgaya |
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| Přispěvatelé: | Institut Català de la Salut, [Mirra S, Manso Y, Serrat R] Department of Cell Biology, Physiology and Immunology, University of Barcelona, 08007 Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain. [Gavaldà-Navarro A] Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain. Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain. [Higuera M] Grup de Recerca en Malalties Hepàtiques, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Salcedo MT] Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Balibrea JM] Unitat de Cirurgia Endocrina, Metabòlica i Bariàtrica, Servei de Cirurgia General, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Mínguez B] Grup de Recerca en Malalties Hepàtiques, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain. Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research obesity neoplasias::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias hepáticas::carcinoma hepatocelular [ENFERMEDADES] Otros calificadores::Otros calificadores::/inducido químicamente [Otros calificadores] SOX9 Biology medicine.disease_cause lcsh:RC254-282 Article Fetge - Càncer - Tractament 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation NAFLD medicine Obesity HCC Gene knockdown lipotoxicity lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 030104 developmental biology Neoplasms::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Liver Neoplasms::Carcinoma Hepatocellular [DISEASES] Oncology Lipotoxicity Cell culture 030220 oncology & carcinogenesis Hepatocellular carcinoma Other subheadings::Other subheadings::/chemically induced [Other subheadings] Hepatic stellate cell Cancer research Alex3 Carcinogenesis |
| Zdroj: | Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona Cancers Scientia Volume 13 Issue 5 Cancers, Vol 13, Iss 1110, p 1110 (2021) |
| Popis: | Simple Summary An excess fat in the liver enhances the susceptibility to hepatic cancer. We found that Armcx3, a protein only known to date to play a role in neural development, is strongly increased in mouse liver in response to lipid availability and proliferation-inducing insults. In patients, the levels of hepatic Armcx3 are also increased in conditions of high exposure of the liver to fat. We wanted to determine the role of Armcx3 in the hepatocarcinogenesis favored by a high-fat diet. We generated mice with genetically driven suppression of Armcx3, and we found that they were protected against experimentally induced hepatic cancer, especially in conditions of a high-fat diet. Armcx3 was also found to promote hepatic cell proliferation through the interaction with Sox9, a known proliferation factor in hepatocellular carcinoma. Armcx3 is identified as a novel factor in meditating propensity to liver cancer in conditions of high hepatic lipid insults. Abstract ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult. |
| Databáze: | OpenAIRE |
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