The role of Myc in the development of hepatocellular carcinoma

World-wide, hepatocellular carcinoma (HCC) is among the most common cancers and frequently overexpresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC in which Myc can be rapidly induced, silenced and re-espressed, we have 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 software tool was developed to allow continued analyses of these and other transcriptional profiles (see: https://prochownik.pitt.edu/hcc. Collectively, these studies define the metabolic, biochemical, and molecular events accompanying HCC evolution, regression, and recurrence in the absence of any potentially confounding therapies. We are continuing to refine this model and are currently exploring how various dietary alterations such as long-and medium-chain high fat diets impact the initiation and progression of these tumors and the associated metabolic re-wiring that accompanies tumorigenesis.

Patterns of gene expression changes during HCC evolution. A, Differentially expressed transcripts. Numbers in parentheses indicate the number of significant gene expression differences between the indicated samples and control livers, per DESeq FDR-adjusted q < 0.05. (n) = 5 samples/group. Transcripts that were over-expressed relative to control liver are colored orange, and those that were underexpressed are colored green. B, Super pathways of gene expression changes duringHCC evolution, regression and recurrence. Differentially expressed transcripts from A were analyzed with Ingenuity Pathway Analysis (IPA; http://www.ingenuity.com), which identified a total of 205 pathways significantly involved across the experimental groups. Individual pathways identified by an IPA comparison of each experimental group with control liver are represented by circles, sized by -log2(p) and colored according to their predicted activation or inhibition (positive or negative Z-score, respectively). Pathways without prediction information from IPA are colored grey. These individual pathways were grouped into 13 super pathways utilizing IPA’s category scheme. Numbers in parentheses indicate total number of member pathways in each super pathway. As an example, the overall changes seen in D3 livers were dominated by three major super pathways: “cancer signaling/proliferation”, “cell cycle”, and “DNA damage”. Among the member pathway groups contained therein were those comprised of transcripts regulating activities such as Brca1 and ATM signaling; DNA mismatch, base excision and double-stranded DNA breakage repair; cell cycle control of DNA replication and G2/M checkpoint regulation. To access super pathways interactively and to explore their component pathway groups and transcripts, see https://prochownik.pitt.edu/hcc.