Abstract
Hepatocellular carcinoma (HCC) is a common cancer that frequently overexpresses 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 sequence 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 was 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 accompanyingHCCevolution, regression, and recurrence in the absence of any potentially confounding therapies.
Highlights
Hepatocellular carcinoma (HCC) is a common cancer that frequently overexpresses the c-Myc (Myc) oncoprotein
Cell cycle analyses performed on nuclei isolated from initial and recurrent tumors showed distinctly different patterns compared with livers and with one another
We found excellent agreement with all tested transcripts. These studies demonstrate that the metabolic and molecular alterations associated with HCC pathogenesis and evolution mediated by Myc overexpression occur gradually, sequentially, and cumulatively
Summary
In contrast to a previous report [22], liver weights remained unchanged for at least 1 week following Myc induction. Recurrent tumors showed a greater fraction of S-phase cells and a more disperse DNA distribution, suggesting that many of the nuclei were aneuploid, despite the known clonal derivation of these from the initial tumors [22]. All tumors resembled moderately differentiated HCCs with numerous mitotic cells observed in most high-power fields (supplemental Fig. S1D) [22] Both initial and recurrent tumors expressed high Myc levels (Fig. 1A and supplemental Fig. S2A). YAP was highly up-regulated in and remained confined to initial and recurrent tumors, expression in the latter group was lower This suggested that, at least in initial tumors, the deregulation of YAP and -catenin was more dependent on sustained Myc expression than on the actual tumor environment. It further indicated distinct biochemical differences between initial and recurrent tumors with regard to the expression of these two critical oncoproteins
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