Sequential Adaptive Changes in a c-Myc-Driven Model of Hepatocellular Carcinoma [Metabolism]

Hepatocellular carcinoma (HCC) is a common cancer that frequently over-expresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical and molecular changes accompanying HCC progression, regression and recurrence. These involved altered rates of pyruvate and fatty acid β-oxidation and the likely re-directing of glutamine into biosynthetic rather than energy-generating pathways. Initial tumors also showed reduced mitochondrial mass and differential contributions of electron transport chain Complexes I and II to respiration. The uncoupling of Complex II's electron transport function from its succinate dehydrogenase activity also suggested a mechanism by which Myc generates reactive oxygen species. RNA-Seq studies revealed an orderly progression of transcriptional changes involving pathways pertinent to DNA damage repair, cell cycle progression, insulin-like growth factor signaling, innate immunity and further metabolic re-programming. Only a subset of functions deregulated in initial tumors were similarly deregulated in recurrent tumors thereby indicating that the latter can "normalize" some behaviors to suit their needs. An interactive and freely available software tool was developed to allow continued analyses of these and other transcriptional profiles. Collectively, these studies define the metabolic, biochemical and molecular events accompanying HCC evolution, regression and recurrence in the absence of any potentially confounding therapies.

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