Tissue Specific Regulation of Diabetes-Associated Cancer Growth

糖尿病相关癌症生长的组织特异性调节

• 批准号: 9070628
• 负责人: OLGA I STENINA
• 金额: $ 32.89万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9070628
• 关键词: Affect; Angiogenic Proteins; Animal Cancer Model; Animals; Antineoplastic Agents; Bladder; Breast; Breeding; Cancer Model; Cardiomyopathies; Cells; Colon Carcinoma; Cultured Cells; Data; Diabetes Mellitus; Diabetic Angiopathies; Diabetic mouse; Endometrial Carcinoma; Goals; Growth; Health; Hepatic; Human; Hyperglycemia; Incidence; Ischemia; Kidney; Kidney Diseases; Liver; Long-Term Effects; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Mediating; MicroRNAs; Microvascular Dysfunction; Modeling; Molecular; Morphology; Myocardium; Neuropathy; Organ; Pancreas; Pathway interactions; Patients; Physiologic Neovascularization; Prevention; Production; Prostate; Regulation; Retina; Retinal Diseases; Skin; Specificity; Testing; Therapeutic; Therapeutic Intervention; Thrombospondin 1; Tissues; Up-Regulation; Wound Healing; angiogenesis; cancer cell; cancer therapy; diabetic; diabetic patient; in vivo; malignant breast neoplasm; mouse model; neovascularization; novel; outcome forecast; prevent; prostate cancer model; research study; response; tumor; tumor growth; tumor progression; type I and type II diabetes

DESCRIPTION (provided by applicant): Diabetes is associated with increased incidence of several cancers (e.g., breast, bladder, pancreas, liver) and decreased incidence of others (e.g., prostate). We suggest that the tissue-specific association with cancers is caused by a tissue-specific regulation of angiogenesis in diabetic patients. A well-known aberrant angiogenesis of diabetes (increased neovascularization in some tissues, e.g., retina and kidney, and deficient angiogenesis causing ischemia in others, e.g., skin and myocardium) has been recognized for many years and is the cause of diabetic microvascular complications (retinopathy, neuropathy, cardiomyopathy, and nephropathy). However, the molecular mechanisms of the tissue-specific diabetic angiogenesis are unknown. We have discovered a novel tissue-specific mechanism that is activated by hyperglycemia: the levels of microRNA-467 (miR-467) are upregulated in response to hyperglycemia, miR-467 inhibits production of a potent anti-angiogenic protein thrombospondin-1 (TSP-1), and, as a result, angiogenesis is increased in a tissue-specific manner. Our preliminary data identified miR-467 as a regulator of TSP-1 production and angiogenesis in response to hyperglycemia, established a correlation between hyperglycemia-induced tumor growth and miR-467 and TSP-1 in vivo, confirmed the effect of miR-467 on angiogenesis in vivo and the effect of miR-467 antagonist on hyperglycemia-induced tumor growth. The overall goals of this project are: 1) characterizing the novel tissue-specific pathway activated by hyperglycemia and controlling angiogenesis and cancer growth in the in vivo diabetic mouse models and in human diabetic cancer tissues and 2) demonstrating that miR-467 is a key regulator of this pathway and can be targeted to control the hyperglycemia-induced tumor growth. The hypothesis that the tissue-specific stimulation of cancer growth by hyperglycemia is mediated by a tissue-specific upregulation of miR-467 and silencing of TSP-1 production and that the hyperglycemia-induced tumor growth can be prevented in a tissue-specific manner by neutralizing of miR-467 will be tested in three Specific Aims: 1. To demonstrate the correlation between miR-467, TSP-1 and cancer angiogenesis in human diabetic cancer tissues. 2. To prevent hyperglycemia-induced breast cancer growth in vivo using systemic delivery of antagomiR-467. 3. To demonstrate the tissue-specificity of the effects of miR-467 antagonist. The tissue-specific mechanism of hyperglycemia-induced angiogenesis that we have discovered provides a breakthrough explanation for the well-documented but poorly understood association between hyperglycemia and several cancers and suggests a new target for the prevention and treatment of cancers in diabetic patients. This mechanism can be targeted in a tissue-specific manner without affecting the physiological angiogenesis. The proposed plan will demonstrate this pathway in vivo in animal diabetes and cancer models and in human cancer tissues and will assess the efficacy of miR-467 antagonist in preventing hyperglycemia-induced cancer growth.

描述（由申请人提供）：糖尿病与几种癌症（例如乳腺癌，膀胱，胰腺，肝脏，肝脏）的发病率增加和其他人的发病率有关（例如前列腺）。我们建议，组织特异性与癌症的关联是由糖尿病患者血管生成的组织特异性调节引起的。 A well-known aberrant angiogenesis of diabetes (increased neovascularization in some tissues, e.g., retina and kidney, and deficient angiogenesis causing ischemia in others, e.g., skin and myocardium) has been recognized for many years and is the cause of diabetic microvascular complications (retinopathy, neuropathy, cardiomyopathy, and nephropathy).但是，组织特异性糖尿病血管生成的分子机制尚不清楚。 We have discovered a novel tissue-specific mechanism that is activated by hyperglycemia: the levels of microRNA-467 (miR-467) are upregulated in response to hyperglycemia, miR-467 inhibits production of a potent anti-angiogenic protein thrombospondin-1 (TSP-1), and, as a result, angiogenesis is increased in a tissue-specific manner.我们的初步数据将miR-467鉴定为对高血糖的TSP-1产生和血管生成的调节剂，在高血糖诱导的肿瘤生长与miR-467和TSP-1 IN VIVO之间建立了相关性，证实了miR-467对Mir-467对摄影的影响mir-467的影响miR-467效应的效果。 The overall goals of this project are: 1) characterizing the novel tissue-specific pathway activated by hyperglycemia and controlling angiogenesis and cancer growth in the in vivo diabetic mouse models and in human diabetic cancer tissues and 2) demonstrating that miR-467 is a key regulator of this pathway and can be targeted to control the hyperglycemia-induced tumor growth.高血糖对癌症生长的组织特异性刺激的假说是由组织特异性上调miR-467和对TSP-1产生的沉默的假说，并且可以在MiR-467中中和3在三个特定的特定方面进行中和3的肿瘤生长，以在组织中进行中和 - 在三个特定的特定方面进行中和3的肿瘤生长。人类糖尿病癌组织中的癌症血管生成。 2。使用全身递送Antagomir-467，为防止高血糖诱导的体内乳腺癌生长。 3。证明miR-467拮抗剂的作用的组织特异性。我们发现的高血糖诱导的血管生成的组织特异性机制为高血糖和几种癌症之间有据可查但知之甚少的关联提供了突破性的解释，并提出了对糖尿病患者癌症预防和治疗的新目标。该机制可以以组织特异性的方式靶向，而不会影响生理血管生成。拟议的计划将在动物糖尿病和癌症模型以及人类癌组织中证明这种途径在体内，并将评估miR-467拮抗剂在预防高血糖诱导的癌症生长方面的疗效。