Studies on the Carcinogenic Mechanisms of Glucose Transporters in Gastrointestinal Cancer Cells and Its Clinical Therapeutic Applications

Gastro-Intestinal (GI) cancer is a term for the group of cancers that affect the digestive system which is the most common form of cancer in Taiwan. According to the Ministry of Health and Welfare Department of the Health and Vital Statistics, cancer ranks first in the top ten causes of death continued where GI cancers continued ranking 3rd major cause of cancer death accounting for all cancers mortality in year 2014. Cancer of the GI is difficult to cure unless it is found at an early stage. However, the early GI cancer causes few symptoms, the disease is usually advanced when the diagnosis is made. Generally, the prognosis of GI cancer is poor, due to the tumor has often metastasised by the time of finding. Therefore, a better strategy for patient with GI cancer is still an important issue in clinical treatment. Cancer cells are known to have enhanced metabolism, and high glucose requirements as well as glucose uptake. In mammalian cells, carriage of glucose across the plasma membrane is the first rate-limiting step for glucose metabolism and is mediated by facilitative glucose transporter (GLUT) proteins. It has been indicated that glucose transporter (GLUT) is overexpressed in several different tumor types. In addition, increased expression has been shown to correlate with tumor aggressiveness, metastasis, and patient survival. Moreover, the studies show that oncogenes and tumor suppressor genes participating in the metabolic switch. Thus, these imply that GLUT expression is important in GI cancer tumorigenesis. In this 2-year eclectic-designed experiment, we hope to find out the correlation between GLUTs expression and clinical characteristics in human GI cancer, evaluate a therapeutic stratagem by using GLUT knock-down, overexpression, inhibitors, and potential natural compounds in gastrointestinal carcinoma cells. 1st year proposal: Study on the characterization of the GLUTs gene phenotype and its biological roles in human gastrointestinal carcinoma tissues in Taiwan. Aim-1: More than 150 cases will be involved in the study. Quantitative analysis of GLUTs expression levels by LCM/real time PCR technique in human gastrointestinal carcinoma tissues. Aim-2: Studies on the molecular mechanisms of GLUT si RNA and inhibitors-mediated antitumor effects. In addition, GLUT overexpression (pcDN5/TO) system will also established to provide the opposite evidences 表C011 共 2 頁第 1 頁 to compare the si RNA system. Also, the roles of transcriptional factors involved in GLUT mediated gastrointestinal r cancer carcinogenesis can also be addressed. Aim-3: Studies on the molecular mechanisms of potential compounds and GLUT inhibitors-mediated antitumor effects potential natural compounds, such as EGCG、Inotilone、Se-Methyl-L-Selnocystein, can be used as an antagonist for GLUTs, which may reduce the gastrointestinal cancer growth. 2nd year proposal: Study on the roles of GLUT involved in gastrointestinal cancer tumorigenesis in human gastrointestinal cancer cell-xenografted tumor model. Aim 1. To Establish of animal experimental platforms for studying the GLUT knock-down and GLUT specific inhibitors in gastrointestinal cancer cells. In study the best protocols of drug administration will be examined and other GLUT family will be also considered in gastrointestinal cancer cells. Aim 2: Evaluation of the antitumor efficacy by combine treatment of GLUT knock-down, GLUT inhibitors, and potential natural compounds with clinical used anticancer agents.