We have published that eliminating a particular RNA splicing factor SRSF3 in hepatocytes causes chronic liver damage, disruptions in glucose and lipid metabolism, inflammation, fibrosis, and eventually liver cancer. So the loss of the splicing factor does not cause tumors but rather creates a pre-disposition to cancer, similar to a tumor suppressor gene. We have since shown that loss of SRSF3 is found in early liver disease in both humans and mice, in addition to being lost in liver cancer which we had shown previously. While the pathological changes that occur during the progression of fatty liver disease to steatohepatitis and cirrhosis have been well documented, we still do not know why some people can maintain relatively benign fatty livers while others progress to more serve liver disease including liver cirrhosis and cancer. Based on extensive preliminary data, we have found that the SRSF3 protein has a short half-life and its levels are acutely regulated by proteosomal degradation. This is not the usual ubiquitin mediated pathway but rather a novel pathway involving conjugation to the NEDD8 protein in response to lipid-induced stress. We believe that SRSF3 may be the gatekeeper that determines whether liver disease progresses or is stable. An individual?s susceptibility to progression is determined by the susceptibility of SRSF3 to stress-induced degradation. So we are proposing a comprehensive series of experiments to understand how SRSF3 is degraded in response to stress and whether stabilizing SRSF3 and preventing its degradation can halt the progression to NASH, cirrhosis and liver cancer. These studies will address key questions concerning the fundamental biological process of protein homeostasis and carcinogenesis and will integrate biochemical, cell and molecular biological experiments with physiological studies in mice lacking specific splicing factors in liver. We will determine the components of the E3-ligase complex that targets SRSF3 for neddylation, the pathway leading to destruction of SRSF3, and how the balance of SRSF3 conjugation and deconjugation is maintained. We investigate whether expressing a degradation-resistant SRSF3 or blocking neddylation in mice will prevent the progression of early liver disease to inflammation, fibrosis and cirrhosis, and we will determine whether this approach prevents liver cancer or can be used to reverse liver cancer in mice.
More than 700,000 people are diagnosed with liver cancer and 600,000 people die each year worldwide; the incidence is increasing in the US and it is estimated that 42,220 new cases will be diagnosed and 30,200 people will die of liver cancer in the next year. Part of the increased incidence in the US is thought to be due to HCV infections acquired during the 1960s and 1970s but aside from viral infection, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and cirrhosis are major risk factors for liver cancer. The 5-year survival rate is only 18% underscoring the lack of effective therapies in liver cancer so a detailed understanding of the mechanisms involved in triggering liver disease and hepatocellular carcinoma would greatly help the prevention and treatment of liver cancer.
