Translational Relevance and Mechanism of Glucose Transporter 3 in Colon Cancer Metastasis

Colon cancer is the third most common cancer in the world and the second most common cause of cancer-related mortality. Metastasis in colon cancer is the leading cause of poor prognostic outcomes. In order to find novel biomarker for metastatic colon cancer, we collected and analyzed primary and liver metastatic colon cancer tissues. Interestingly, we found that expression of glucose transporter 3 (Glut3) was drastically elevated in liver metastatic colon cancer tissue, and overexpression of Glut3 associates with poor prognosis. We also found that expression of Glut3 was increased in established metastatic colon cancer cells. Treatment with high glucose in metastatic colon cancer cells induces Hippo-YAP activation, conversely, the addition of glycolysis inhibitor 2-deoxyglucose suppressed Hippo-YAP, with concomitantly decreased in Glut3 expression. Moreover, inhibition of YAP down-regulated expression of Glut3, and YAP/TAZ was positive correlation with Glut3 in colon cancer patients. These data suggest a reciprocal regulation by Glut3 and YAP may enhance malignant progression in colon cancer. Because many epidemiological studies have pointed out that obesity, diabetes, or high sugar uptakes are the risks of colon cancer. Aberrant cancer metabolism, especially aerobic glycolysis, also known as the Warburg effect is one recognized metabolic hallmark of cancer. However, there is no evidence reporting the role of Glut3 in tumor metastasis and cancer stemness. In order to identify the role and regulatory mechanism of Glut3 in colon cancer metastasis, and to validate its potential as a novel cancer biomarker, three specific aims will be further addressed in this research proposal: Aim 1: Identifying the roles of Glut3 to the contribution of invasiveness, metastasis, and stemness in colon cancer. Aim 2: Investigating molecular mechanism underlying glucose and Glut3-mediated tumor progression. Aim 3: Validating Glut3 is a novel biomarker and therapeutic target for metastatic colon cancer. The study will provide a novel and valuable resource for scientific knowledge and translational medicine to understand increased sugar uptake promotes malignant progression of colon cancer. These achievements will make a significant impact in the development of novel technology and clinical application for human disease and biopharmaceutics in Taiwan.