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名美国人被诊断出患有RCC，包括军事人员，其家人和美国退伍军人人口。预计将诊断出54,390例新的肾癌新病例，2012年在美国13,010例受影响的人将死亡。大约50％的转移性RCC患者的存活率不到一年。此外，癌症对糖尿病患者的死亡率约为10％。在美国，有超过2300万人患有糖尿病，到2025年预测将增加到2500万，这可能会增加包括肾细胞癌在内的实体瘤风险。最近，我们表明，有25.4％的肾癌患者患有来自圣安东尼奥医院的糖尿病病史。糖尿病增强某些发展癌症途径的机制在很大程度上未知。此外，没有有效的生物标志物可以早期检测糖尿病患者的癌症发病率。假设：我们假设慢性暴露于高葡萄糖（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，TUBERIN，TUBERIN，TUBERIN，TUBERIN，TUBERIAN（由TSC2蛋白质编码）。结核素的失活导致（1）雷帕霉素复合物1（MTOR）mTORC1的哺乳动物靶标激活块和降解胰岛素受体底物-1（IRS-1）和（2）MTOC2激活MTOC2通过反馈回路激活AKT。另一方面，MTORC1/C2的激活导致DNA修复酶的下调8-OXOG-DNA糖基化酶（OGG1）和Poly（ADP-核糖）聚合酶（PARP）灭活细胞凋亡。 OGG1和PARP的灭活导致氧化DNA，8-OXODG的积累。 DNA损伤（8-oxoDG）增强了DNA甲基化和诱变，并使肾脏和其他器官易于癌症。为了更好地理解生物学合理性的机制，高血糖和/或高胰岛素血症增加了癌症风险，并找到糖尿病患者早期检测到癌症的生物标志物，我们提出了以下特定目的。具体目的1：确定高葡萄糖或高葡萄糖+高胰岛素的慢性暴露可调节细胞存活/凋亡/增殖和DNA损伤/修复途径，以促使DNA甲基化/突变的近端管细胞中的突变，其中肾细胞癌的起源。具体目的2：探索高胰岛素血症+高血糖对TSC2 +/-肾细胞癌发育率和严重程度的影响，在我们的新TSC2+/ - /DBDB小鼠模型（II型糖尿病模型）中。特定目的3：确定在细胞培养和动物中鉴定出对糖尿病患者的高血糖或高胰岛素血症+高血糖的相关作用。此外，找到一个可用作糖尿病患者癌症的生物标志物的候选基因。