Serra, Marina and Di Matteo, Mario and Serneels, Jens and Pal, Rajesh and Cafarello, Sarah Trusso and Lanza, Martina and Sanchez-Martin, Carlos and Evert, Matthias and Castegna, Alessandra and Calvisi, Diego Francesco and Mazzone, Massimiliano and Columbano, Amedeo (2022) Deletion of Lactate Dehydrogenase-A Impairs Oncogene-Induced Mouse Hepatocellular Carcinoma Development. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, 14 (3). pp. 609-624. ISSN 2352-345X,
Full text not available from this repository. (Request a copy)Abstract
BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a multistep process whereby abnormally proliferating cancer cells undergo extensive metabolic reprogramming. Metabolic alterations in hepatocarcinogenesis depend on the activation of specific oncogenes, thus partially explaining HCC heterogeneity. c-Myc oncogene overexpression, frequently observed in human HCCs, leads to a metabolic rewiring toward a Warburg phenotype and production of lactate, resulting in the acidification of the extracellular space, favoring the emergence of an immune-permissive tumor microenvironment. Here, we investigated whether Ldha genetic ablation interferes with metabolic reprogramming and HCC development in the mouse. METHODS: We characterized the metabolic reprogramming in tumors induced in C57BL/6J mice hydrodynamically cotrans-fected with c-Myc and h-Ras. Using the same experimental model, we investigated the effect of Ldha inhibition-gained through the inducible and hepatocyte-specific Ldha knock-out-on cancer cell metabolic reprogramming, number and size of HCC lesions, and tumor microenvironment alterations. RESULTS: c-Myc/h-Ras-driven tumors display a striking glycolytic metabolism, suggesting a switch to a Warburg phenotype. The tumors also exhibited enhanced pentose phosphate pathway activity, the switch of glutamine to sustain glutathione synthesis instead of the tricarboxylic acid cycle, and the impairment of oxidative phosphorylation. In addition, Ldha abrogation significantly hampered tumor number and size together with an evident inhibition of the Warburg-like meta-bolic feature and a remarkable increase of CD4(+) lymphocytes compared with Ldha wild-type livers. CONCLUSIONS: These results demonstrate that Ldha deletion significantly impairs mouse HCC development and suggest lactate dehydrogenase as a potential target to enhance the ef-ficacy of the current therapeutic options.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | COMPLEX-II; RAT-LIVER; CANCER; SYNTHETASE; METABOLISM; EXPRESSION; TARGET; GROWTH; GENE; HCC; c-Myc; Ldha; Metabolic Reprogramming; TME |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Jan 2024 14:03 |
| Last Modified: | 29 Jan 2024 13:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58307 |
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