Title: Starving Livers of glucose for HCC prevention and treatment
Funder: Guts UK

Abstract: In more than 90% of patients, hepatocellular carcinoma (HCC), the most common type of primary liver cancer, develops in the settings of chronic liver disease such as cirrhosis. At the cellular level, cirrhosis develops after multiple rounds of hepatocyte death, inflammatory responses and compensatory hepatocyte proliferation, resulting in the formation of the regenerative nodules surrounded by fibrous bands. These regenerative nodules consist of a mixed population of highly proliferative hepatocytes and death-resistant hepatocytes that, following genetic damage, are likely to develop into dysplastic nodules, leading to the development of HCC. Therefore, hepatocyte death is a central feature in the progression of chronic liver diseases and development of HCC. However, one needs to carefully distinguish between cell death occurring in non-transformed hepatocytes and cell death occurring in transformed hepatocytes, as these have opposite functional consequences. Cell death in non-transformed hepatocytes represents a tumour-promoting mechanism, mediated by increased compensatory proliferation, regeneration, fibrosis and inflammation. In contrast, cell death in transformed hepatocytes limits development of HCC. Accordingly, transformed hepatocytes often undergo a selection process (through the activation of anti-apoptotic pathways) that allows them to escape apoptosis and accumulate in the liver giving rise to HCC. However, these anti-apoptotic signals are largely unknown. Cellular metabolism plays an important role in cell survival, proliferation, and growth. We and others have shown that the progression of cirrhosis to HCC is accompanied with a progressive metabolic shift from gluconeogenesis to glycolysis that persists into carcinoma. Unlike healthy livers, both cirrhotic and HCC livers rely on aerobic glycolysis (an accelerated consumption of glucose and production of lactate under aerobic conditions) to produce energy and sustain cell survival (as opposed to cell death), suggesting, therefore, that inhibition and control of aerobic glycolysis may have an impact on HCC development. We have recently shown that PARP14 is a master regulator of aerobic glycolysis and a fundamental anti-apoptotic factor needed for the survival of cancer cells, including HCC cells. While PARP14 is under-expressed in healthy livers, it is upregulated in both cirrhotic (precancerous) and HCC livers. Interestingly, our preliminary data indicate that PARP14 is upregulated in regenerating mouse livers following hepatic injury induced by either hepatotoxins or carcinogens, but not after surgical liver resection (also known as partial hepatectomy). This suggests that the PARP14-mediated regulation of aerobic glycolysis is not essential for ‘healthy’ liver regeneration post-resection but may be essential for survival and compensatory proliferation of damaged hepatocytes. In order to determine the contribution of PARP14 to the metabolic shift and hepatocyte survival under conditions of liver repair or malignant transformation, we have recently generated conditional PARP14-knockout mice to test the effect of gene depletion in pre-clinical mouse models of hepatic tumorigenesis and liver fibrosis. These studies may pave a way for development of preventive and early therapeutic strategies against HCC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS