Determining Unique Metabolic features of Hepatocellular Carcinoma.

项目摘要 作为一个主要的代谢器官，肝脏催化膳食糖，主要包括葡萄糖 和果糖。肝细胞癌（HCC）增强糖酵解，无论氧 供应然而，与正常肝组织相比，HCC是否改变了果糖 代谢，如果是这样，这种改变的碳水化合物代谢是否有助于 肿瘤发生是未知的。我们的初步结果显示，正常肝细胞， 具有高的果糖代谢率，表达高活性的果糖激酶（KHK）异构体KHK- 果糖代谢中的限速酶。相比之下，HCC细胞具有低得多的 果糖代谢率，而KHK亚型的表达是由 KHK基因的异质核核糖核蛋白H1/2依赖性选择性剪接， 导致从高活性KHK-C到低活性KHK-A同种型表达的转变。 重要的是，我们证明了KHK-A的表达是生产核苷酸所必需的。 和来自糖酵解的核苷酸。我们假设KHK的异常剪接 协调果糖代谢和糖酵解依赖性从头核酸的调节 酸的合成，促进HCC的发展。为了验证这一假设，我们将追踪三个 具体目的：1）确定KHK的选择性剪接在肝癌调控中的作用 代谢，2）确定选择性KHK剪接的作用和KHK-A- 介导的PRPS 1磷酸化在肝细胞肿瘤生长中的作用，以及3）确定 果糖代谢在肝细胞肿瘤生长中的作用所提出的研究是有意义的 因为它可能导致药物方法通过阻断HCC代谢来中断HCC代谢， KHK-A的功能。反过来，这将提高HCC治疗的疗效。

PROJECT SUMMARY 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.