As a major metabolic organ, the liver catalyzes dietary sugar, primarily encompassing glucose and fructose. Hepatocellular carcinoma (HCC) enhances glycolysis regardless of the oxygen supply. However, whether HCC, in contrast with normal liver tissue, has altered fructose metabolism and, if so, whether this altered carbohydrate metabolism contributes to tumorigenesis are unknown. Our preliminary results revealed that normal hepatocytes, which have high fructose metabolism rates, express the high-activity fructokinase (KHK) isoform KHK- C, a rate-limiting enzyme in fructose metabolism. In contrast, HCC cells have a much lower fructose metabolism rate, and this stitch of KHK isoform expression is mediated by heterogeneous nuclear ribonucleoprotein H1/2-dependent alternative splicing of the KHK gene, resulting in a switch from high-activity KHK-C to low-activity KHK-A isoform expression. Importantly, we demonstrated that KHK-A expression is required for production of nucleotides and nucleotide acid derived from glycolysis. We hypothesize that aberrant splicing of KHK coordinates the regulation of fructose metabolism and glycolysis-dependent de novo nucleic acid synthesis to promote HCC development. To test this hypothesis, we will pursue three specific aims: 1) determine the role of alternative splicing of KHK in the regulation of HCC metabolism, 2) determine the role of alternative KHK splicing and the significance of KHK-A? mediated PRPS1 phosphorylation in hepatocellular tumor growth, and 3) determine the role of fructose metabolism in hepatocellular tumor growth. The proposed research is significant because it may lead to pharmaceutical approaches to interrupting HCC metabolism by blocking the function of KHK-A. In turn, this would improve the efficacy of HCC treatment.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. However, whether HCC, in contrast with normal liver tissue, alters fructose metabolism is unknown. In the proposed study, we will elucidate the mechanisms that underlie the coordinated regulation of glycolysis and fructose metabolism in HCC and this research may help us identify molecular markers of prognosis for HCC and lead to HCC therapies that are more effective than those used currently.
