Determining Unique Metabolic features of Hepatocellular Carcinoma.

项目总结 作为主要的代谢器官，肝脏催化饮食中的糖，主要包括葡萄糖。 还有果糖。肝细胞癌(肝细胞癌)促进糖酵解，与氧气无关 供给。然而，与正常肝组织相比，肝癌是否改变了果糖 代谢，如果是这样的话，这种改变的碳水化合物代谢是否有助于 肿瘤的发生机制尚不清楚。我们的初步结果显示，正常的肝细胞， 有较高的果糖代谢率，表达高活性果糖激酶(KHK)亚型KHK- C，果糖代谢中的限速酶。相比之下，肝细胞癌细胞的 果糖代谢率，这一针的KHK亚型表达是由 依赖核糖核蛋白H1/2的KHK基因的异质性选择性剪接， 导致从高活性KHK-C转换为低活性KHK-A亚型表达。 重要的是，我们证明了KHK-A的表达是产生核苷酸所必需的 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的从头核的调节 酸合成促进肝细胞癌发展。为了验证这一假设，我们将研究三个问题 具体目的：1)确定KHK选择性剪接在肝癌调控中的作用 代谢，2)确定KHK选择性剪接的作用和KHK-A- 介导的PRPS1磷酸化在肝细胞肿瘤生长中的作用，以及3)确定 肝细胞肿瘤生长中的果糖代谢。这项拟议的研究具有重要意义 因为它可能导致通过阻断肝癌代谢来阻断肝癌代谢的药物方法 KHK-A的功能。反过来，这将提高肝细胞癌的治疗效果。

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.