Page 86 - ebook HCC

84 PROGRAMME AND ABSTRACTS GENEVA, SWITZERLAND EASL HCC SUMMIT 85
FEBRUARY 13 - 16, 2014

THE ROLE OF C-MYC IN CHRONIC LIVER INJURY
AND HEPATOCARCINOGENESIS

Arndt Vogel 1
1 Gastroenterology, Medical School Hannover, Hannover, Germany

Corresponding author’s e-mail: vogel.arndt@mh-hannover.de

Elevated and/or deregulated expression of c-myc has been detected in many human One of the key functions of c-myc is its ability to regulate the expression of genes that are
cancers, including hepatocellular carcinomas. Given the fact that most tumors are detected required for somatic cell cycle progression and most in vitro and in vivo studies suggest that
at an advanced stage, it is difficult to ascertain whether c-myc plays a more important role inducing uncontrolled proliferation is one of the most important oncogenic consequences
in tumor initiation or in tumor progression. In embryonic and neonatal murine livers, c-myc of deregulated c-myc expression. In addition to its function in driving the cell cycle and
cell differentiation, c-myc was also shown to participate in the apoptotic response. In the
BASIC SPEAKERS ABSTRACTS mice develop tumors only after a prolonged latency suggesting context-specific effects of or sensitize cells to apoptosis. Finally, it has become increasingly clear that metabolic BASIC SPEAKERS ABSTRACTS
overexpression induces marked cell proliferation and the immediate onset of neoplasia. In
absence of survival factors or if cell cycle progression is blocked, c-myc can either induce
contrast, c-myc overexpression in adult livers failed to induce hepatocyte proliferation and
c-myc in hepatocytes. Co-expression of c-myc with other oncogenes such as transforming
changes that accompany transformation are intimately related to the growth abnormalities
growth factor alpha (TGFα) results in a tremendous acceleration of neoplastic development
of malignant cells and that these metabolic changes are necessary to provide the energy
in the liver. The importance of c-myc for tumor maintenance has been shown in mouse
required for rapid cell division. Studies in cancer cells that overexpress c-myc revealed
that c-myc gene could serve as a “master regulator” of cellular metabolism and that c-myc
models with conditional transgene expression systems. Hepatocellular carcinomas usually
arise within the context of chronic liver injury. Most previous studies have continuously
overexpressed c-myc as a transgene in otherwise healthy mice to analyze the role of c-myc
role of c-myc as master regulator of tumor growth suggests that this transcription factor
in tumorigenesis. This approach precludes the investigation of the specific consequences is involved in glycolyis, glutamine metabolism and mitochondrial biogenesis.The central
is an intriguing target for cancer therapies. Moreover, there is evidence for a certain
of c-myc activation during chronic liver injury. C-myc regulates cellular processes through threshold level of c-myc expression, which is required to maintain a tumor phenotype.
positive and negative regulation of multiple target genes by distinct mechanisms, which Down regulating c-myc below a critical level reduced its ability to maintain tumorigenesis
include direct binding to DNA, interacting with other transcription factors and recruiting and induced a shift in gene expression that re-established cell cycle checkpoints, halted
histone acetylases and DNA methyltransferases. Another layer of complexity has emerged protein translation, and promoted apoptosis. Very recently, specific DsiRNA have been
from the binding of Myc – Max heterodimers, thereby disrupting the functions of other developed, which specifically targets c-myc in tumor cells. These DsiRNAs are currently
transcription factors. Finally, c-myc regulates a broad set of miRNAs. Multiple studies have evaluated for their anti-tumor efficacy in different preclinical models.
documented the deregulation of miRNAs in cancer cells. Although altered expression of
specific miRNAs has been shown to promote tumorigenesis, downregulation of global
miRNA abundance seems to contribute to neoplastic transformation due to an increased
expression of proteins with oncogenic potential. There is increasing evidence that c-myc
not only activates specific miRNA clusters, but also leads to a widespread repression of
miRNA by directly binding to their promoter.