MedicalResearch.com Interview with:
Zhimin (James) Lu, M. D., Ph. D
Ruby E. Rutherford Distinguished Professor
Department of Neuro-Oncology
MD Anderson Cancer Center
Houston, TX 77030
MedicalResearch.com: What is the background for this study?
Dr. Lu: Among primary liver cancers, hepatocellular carcinoma (HCC) is the most common histological subtype, accounting for 70-85% of all cases. HCC incidence is increasing in many parts of the world, including developing countries and developed countries such as the United States. HCC has a very poor prognosis, and the overall 3-year survival rate for patients with HCC is approximately 5%. The potentially curative treatments of HCC are resection and liver transplantation. However, most patients with hepatocellular carcinoma present with advanced disease and underlying liver dysfunction and are not suitable candidates for these treatments. Thus, they generally have a poor prognosis, with a median survival time of less than 1 year. The increasing incidence and mortality rates of hepatocellular carcinoma, along with a lack of effective curative treatment options for advanced HCC, have rendered this disease a major health problem worldwide. Thus, a better understanding of HCC tumorigenesis and the development of better diagnostic and therapeutic approaches based on an understanding of the molecular mechanisms that drive hepatocellular carcinoma progression are greatly needed.
The liver, as a major metabolic organ, catalyzes dietary sugar. Dietary sugar encompasses several carbohydrates, including starch, sucrose, and high-fructose corn syrup, each of which is composed of glucose with or without fructose. Starch, which is found in bread and rice, is a glucose polymer. Sucrose is a disaccharide made up of 50% glucose and 50% fructose. High-fructose corn syrup, a common constituent of soft drinks, is a mixture of approximately 40% glucose and 60% fructose. Dietary fructose is also derived from fruits and vegetables. A molecule of glucose has the same caloric value as a molecule of fructose. However, the human body treats these carbohydrates quite differently. Glucose is used directly by tissues such as the muscles and brain as an energy source. Excess glucose is stored in the liver as glycogen. In contrast, dietary fructose, which is epidemiologically linked with obesity and metabolic syndrome, is almost exclusively metabolized by the liver.
Hepatocellular carcinoma cells enhance glucose uptake and lactate production regardless of the oxygen supply, a phenomenon known as the Warburg effect. However, whether fructose metabolism is differentially regulated in hepatocellular carcinoma and normal liver tissue and, if so, the extent to which this altered carbohydrate metabolism contributes to hepatocellular carcinoma development is unknown.
MedicalResearch.com: What are the main findings?
Dr. Lu: We revealed that HCC cells had a much lower fructose metabolism rate than did normal hepatocytes, and this reduced fructose metabolism in hepatocellular carcinoma was mediated by alternative splicing of the ketohexokinase (also known as fructokinase) gene KHK, resulting in a switch from high-activity KHK-C to low-activity KHK-A isoform expression.
Importantly, we demonstrated that in hepatocellular carcinoma cells, KHK-A functioning as a protein kinase phosphorylates and activates phosphoribosyl pyrophosphate synthetases 1 (PRPS1), a rate-limiting enzyme required for the de novo nucleotides and nucleotide acid synthesis. Functional studies demonstrated that KHK-A but not KHK-C expression is required for the de novo nucleic acid synthesis and hepatocellular tumorigenesis, indicating an essential role of KHK-A in hepatocellular carcinoma formation. These results indicate that a change in the aberrant splicing of KHK coordinates the regulation of fructose metabolism and glycolysis to promote hepatocellular carcinoma development.
MedicalResearch.com: What should clinicians and patients take away from your report?
Dr. Lu: Our studies revealed that KHK-A is a unique molecular target for treating liver cancer. We will continuously work on the unique metabolic feature of hepatocellular carcinoma we discovered to identify new diagnostic and therapeutic tools for hepatocellular carcinoma.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation
Xinjian Li, Xu Qian, Li-Xia Peng, Yuhui Jiang, David H. Hawke, Yanhua Zheng, Yan Xia,Jong-Ho Lee, Gilbert Cote, Hongxia Wang, Liwei Wang, Chao-Nan Qian Zhimin Lu
Nature Cell Biology (2016) doi:10.1038/ncb3338
Received 10 May 2015
Accepted 11 March 2016 Published online 18 April 2016
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