Diabetic Complications and Risk of Kidney Cancer

糖尿病并发症和肾癌风险

• 批准号: 8834816
• 负责人: Samy Lewiz Habib
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8834816
• 关键词: 8-hydroxyguanosine; Acceleration; Affect; American; Animals; Apoptosis; Biochemical; Biological; Biological Markers; Breeding; Cancer Patient; Candidate Disease Gene; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cells; Chronic; Colon; Complex; Complications of Diabetes Mellitus; Cyclin D1; DNA; DNA Damage; DNA Methylation; DNA Repair; DNA Repair Enzymes; DNA Sequence Alteration; DNA glycosylase; Data; Development; Diabetes Mellitus; Diagnosis; Down-Regulation; Early Diagnosis; Endometrium; Epithelial; Exposure to; Family member; Feedback; Gene Expression; General Population; Genetic; Glucose; Goals; Hospitals; Hyperglycemia; Hyperinsulinism; IRS1 gene; In Vitro; Incidence; Individual; Insulin; Kidney; Lead; Life; Liver; Malignant Neoplasms; Metastatic Renal Cell Cancer; Military Personnel; Modeling; Mus; Mutagenesis; Mutation; Non-Insulin-Dependent Diabetes Mellitus; OGG1 gene; Organ; Pancreas; Pathway interactions; Patients; Persons; Phosphotransferases; Poly(ADP-ribose) Polymerases; Population; Proliferating Cell Nuclear Antigen; Proteins; Recording of previous events; Regulation; Renal Cell Carcinoma; Renal carcinoma; Risk; Screening for cancer; Severities; Signal Pathway; Signal Transduction; Solid Neoplasm; Survival Rate; TSC2 gene; Testing; Time; Tissues; Tubular formation; Tumor Suppressor Proteins; United States; Urologic Cancer; Veterans; Wild Type Mouse; Woman; biliary tract; cancer risk; db/db mouse; diabetic; diabetic patient; high risk; human TSC2 protein; in vivo; insulin receptor substrate 1 protein; kidney cell; mTOR protein; member; men; mortality; mouse model; oxidative DNA damage; public health relevance; tool; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Every year approximately 40,000 Americans are diagnosed with RCC including military personnel, their family members, and U.S. Veteran population. It is expected that 54,390 new cases of kidney cancer would be diagnosed and 13,010 affected individuals would die in the U.S. in 2012. Approximately 50% of patients with metastatic RCC have a survival rate of less than one year. In addition, cancer contributes approximately 10% to mortality in diabetic patients. More than 23 million persons in the United States with diabetes and predicting by 2025 will be increase to 25 million and that may increase the risk of solid tumors including renal cell carcinoma. We show recently that 25.4 % of kidney cancer patients have history with diabetes from San Antonio Hospitals. The mechanism by which diabetes enhances certain pathways to develop cancer is largely unknown. In addition, there is no valid biomarker for the early detection of the incidence of cancer in diabetic patient. Hypothesis: we hypothesize that the chronic exposure to high glucose (hyperglycemia, HG) and/or insulin (hyperinsulinaemia, HI) activates the cell survival kinase, Akt and lead to inactivates tumor suppressor protein, tuberin (protein encodes by TSC2). Inactivation of tuberin resulted in (1) activation of mammalian target of rapamycin complex 1 (mTOR) mTORC1 to blocks and degrades insulin receptor substrate-1 (IRS- 1) and (2) activation of mTOC2 to activate Akt through feedback loop. On the other hand, activation of mTORC1/C2 resulting in downregulation of the DNA repair enzymes 8-oxoG-DNA glycosylase (OGG1) and poly (ADP-ribose) polymerase (PARP) to inactivates cell apoptosis. Inactivation of OGG1 and PARP resulted in accumulation of oxidative DNA, 8-oxodG. DNA damage (8-oxodG) enhances DNA methylation and mutagenesis and predisposes kidney and other organs to cancer. To better understand the mechanism of biological plausibility by which hyperglycaemia and/or hyperinsulinaemia increasing cancer risk and find a biomarker for early detection of cancer in diabetic patients, we proposed the following specific aims. SPECIFIC AIM 1: To determine the mechanisms by which chronic exposure of high glucose or high glucose+high insulin regulates cell survival/apoptosis/proliferation and DNA damage/repair pathways to prompt DNA methylation/mutations in proximal tubular cells, where renal cell carcinoma originates. SPECIFIC AIM 2: To explore the effect of hyperinsulinemia+hyperglycemia on the rate of development and severity of renal cell carcinoma in TSC2+/- in our new TSC2+/-/dbdb mouse model (model of type II diabetes). SPECIFIC AIM 3: To determine the relevant effect of hyperglycemia or hyperinsulinemia+ hyperglycemia identified in cell culture and animal to diabetic patients. In addition, find a candidate gene(s) that can be used as a biomarker for early detection of cancer in diabetic patients.

描述（由申请人提供）： 每年约有 40,000 名美国人被诊断患有 RCC，其中包括军人、他们的家人和美国退伍军人。预计 2012 年美国将诊断出 54,390 例肾癌新病例，并有 13,010 名受影响者死亡。大约 50% 的转移性肾细胞癌患者的生存率不到一年。此外，癌症约占糖尿病患者死亡率的 10%。美国有超过 2300 万糖尿病患者，预计到 2025 年将增加到 2500 万，这可能会增加患包括肾细胞癌在内的实体瘤的风险。我们最近发现，圣安东尼奥医院 25.4% 的肾癌患者有糖尿病史。糖尿病增强某些癌症发生途径的机制目前尚不清楚。此外，尚无有效的生物标志物可用于早期检测糖尿病患者癌症的发生率。假设：我们假设长期暴露于高血糖（高血糖，HG）和/或胰岛素（高胰岛素血症，HI）会激活细胞存活激酶 Akt，并导致肿瘤抑制蛋白马铃薯蛋白（由 TSC2 编码的蛋白）失活。马铃薯蛋白失活导致 (1) 哺乳动物雷帕霉素靶复合物 1 (mTOR) mTORC1 激活，以阻断和降解胰岛素受体底物 1 (IRS-1) 和 (2) mTOC2 激活，通过反馈环路激活 Akt。另一方面，mTORC1/C2 的激活导致 DNA 修复酶 8-oxoG-DNA 糖基化酶 (OGG1) 和聚 (ADP-核糖) 聚合酶 (PARP) 的下调，从而抑制细胞凋亡。 OGG1 和 PARP 失活导致氧化 DNA 8-oxodG 的积累。 DNA 损伤 (8-oxodG) 会增强 DNA 甲基化和诱变，并使肾脏和其他器官易患癌症。为了更好地了解高血糖和/或高胰岛素血症增加癌症风险的生物学机制，并找到用于糖尿病患者癌症早期检测的生物标志物，我们提出了以下具体目标。具体目标 1：确定长期暴露于高葡萄糖或高葡萄糖+高胰岛素调节细胞存活/凋亡/增殖和 DNA 损伤/修复途径以促进肾细胞癌起源的近端肾小管细胞 DNA 甲基化/突变的机制。具体目标2：在我们新的TSC2+/-/dbdb小鼠模型（II型糖尿病模型）中探讨高胰岛素血症+高血糖对TSC2+/-肾细胞癌的发生率和严重程度的影响。具体目标 3：确定细胞培养物和动物中发现的高血糖或高胰岛素血症+高血糖对糖尿病患者的相关影响。此外，寻找可用作糖尿病患者癌症早期检测的生物标志物的候选基因。