MicroRNAs as Targets for Colon Cancer Chemotherapy

MicroRNA 作为结肠癌化疗的靶点

• 批准号: 8064803
• 负责人: Stephen H. Safe
• 金额: $ 25.98万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-03 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8064803
• 关键词: Accounting; Acids; Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Betulinic Acid; Cancer Cell Growth; Cancer Patient; Cause of Death; Cell Survival; Chemopreventive Agent; Chemotherapy-Oncologic Procedure; Colon Carcinoma; Colorectal Cancer; Curative Surgery; Cytotoxic agent; Data; Developed Countries; Development; Diagnosis; Diet; Disease; Drug Delivery Systems; Environmental Risk Factor; Esters; Gene Expression; Genes; Genetic Markers; Genetic Predisposition to Disease; Growth; Health; Incidence; Inherited; Laboratories; Link; Localized Disease; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; MicroRNAs; Modeling; Molecular Genetics; Mus; Mutation; Neoplasm Metastasis; Nomads; Non-Steroidal Anti-Inflammatory Agents; Oncogenic; Other Genetics; Pathway interactions; Patients; Pharmaceutical Preparations; Proteins; Recurrent disease; Repression; Role; Specificity; Transcript; United States; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2; Xenograft procedure; angiogenesis; cancer cell; colon carcinogenesis; experience; in vivo; multicatalytic endopeptidase complex; novel; overexpression; response; survivin; transcription factor; tumor; tumor growth; tumor specificity

DESCRIPTION (provided by applicant): Colorectal cancer is one of the leading causes of death in most developed countries including the United States. Colon cancer chemotherapy relies on a number of cytotoxic drugs, targeted agents and their combinations, and there is an increasing need to develop alternative drugs targeting specific pathways that inhibit tumor growth, progression and metastasis and induce apoptosis. Specificity proteins (Sps) are transcription factors overexpressed in many tumors, and Sps regulate expression of genes required for cancer cell and tumor growth (p27 suppression), survival (survivin), and angiogenesis (VEGF, VEGFR1 and VEGFR2). Studies in this laboratory have now shown that tolfenamic acid (TA) and betulinic acid (BA) and a novel synthetic triterpenoid acid (ester), namely methyl-2-cyano-3,11-dioxo-18¿-olean-1,12-dien-30-oate (CDODA-Me) induce G2/M growth arrest and proteasome-independent degradation of Sp proteins in colon cancer cells. These effects are directly linked to compound-induced modulation of expression of oncogenic microRNA-27a (mir-27a) and other miRs. Therefore, we hypothesize that TA, BA and CDODA-Me represent a unique class of anticancer agents that target miR-27a and other miRs. The proposed studies will characterize the mechanisms of action and effects resulting from drug-miR interactions in colon cancer. Aim 1 will focus on TA-/BA-/CDODA-Me-miR-27a interactions and investigate the activation of miR-27a-dependent ZBTB10 and Myt-1 expression and their subsequent downstream modulation of Sp and Sp-dependent genes, growth inhibitory, antiangiogenic and proapoptotic responses in colon cancer cells. TA, BA and CDODA-Me also decrease expression of other miRs in colon cancer cells, and these include miR-23a and miR-24-2 which form a cluster with miR-27a. Aim 2 will investigate TA-, BA- and CDODA-Me-miR(23a~24-2) interactions and determine their role in mediating the anticarcinogenic activities of these compounds. Aim 3 will investigate the in vivo anticarcinogenic activity of TA, BA and CDODA-Me in a mouse xenograft and "Min" model for colon cancer and determine the compound-miR interactions. In addition, mice overexpressing miR-27a have been developed as probes for investigating the role of this oncogenic miR in colon carcinogenesis. These studies will provide critical data on the efficacy and mechanisms of action of TA, BA and CDODA-Me as a novel class of anticancer drugs that act through multiple pathways including direct effects on microRNAs and their associated gene transcripts. PUBLIC HEALTH RELEVANCE: Recent studies in this laboratory have identified two structural classes of compounds that induce Sp protein repression in cancers and inhibit cancer cell growth and survival. These compounds include the triterpenoids betulinic acid (BA) and methyl 2-cyano-3,11-dioxo-18¿-olean-1,12-dien-30-oate (CDODA-Me) and the NSAID tolfenamic acid (TA). The studies proposed in this project will focus on the mechanisms of action of these anticancer agents with emphasis on their effects on the oncogenic microRNA-27a (miR-27a) and other miRs and the role in repression of Sp proteins and other critical genes.

描述（由申请人提供）：结直肠癌是包括美国在内的大多数发达国家的主要原因之一。结直肠癌化疗依赖于多种细胞毒性药物、靶向药物及其组合，并且越来越需要这种药物。开发针对抑制肿瘤生长、进展和转移并诱导细胞凋亡的特定途径的替代药物。特异性蛋白 (Sps) 是在许多肿瘤中过度表达的转录因子，Sps 调节癌细胞和肿瘤生长所需基因的表达 (p27)。该实验室的研究现已表明，托芬那酸 (TA) 和桦木酸 (BA) 以及一种新型合成三萜酸（酯），即甲基- 2-氰基-3,11-二氧代-18¿ -olean-1,12-dien-30-oate (CDODA-Me) 可诱导结肠癌细胞中 G2/M 期生长停滞和 Sp 蛋白的蛋白酶体依赖性降解，这些作用与化合物诱导的致癌基因表达调节直接相关。 microRNA-27a (mir-27a) 和其他 miR 因此，我们发现 TA、BA 和 CDODA-Me 代表了一类独特的靶向 miR-27a 和 miR-27a 的抗癌药物。拟议的研究将描述结肠癌中药物-miR 相互作用的作用机制和影响，目标 1 将重点关注 TA-/BA-/CDODA-Me-miR-27a 相互作用并研究 miR-的激活。结肠癌细胞中 27a 依赖性 ZBTB10 和 Myt-1 的表达及其随后对 Sp 和 Sp 依赖性基因的下游调节、生长抑制、抗血管生成和促凋亡反应。 CDODA-Me 还会降低结肠癌细胞中其他 miR 的表达，其中包括 miR-23a 和 miR-24-2，它们与 miR-27a 形成簇，Aim 2 将研究 TA-、BA- 和 CDODA-Me-miR。 (23a~24-2)相互作用并确定它们在介导这些化合物的抗癌活性中的作用目标3将研究TA、BA和的体内抗癌活性。小鼠异种移植物和结肠癌“Min”模型中的 CDODA-Me 并确定化合物-miR 相互作用。此外，过表达 miR-27a 的小鼠已被开发为研究这种致癌 miR 在结肠癌发生中的作用的探针。将提供关于 TA、BA 和 CDODA-Me 作为一类新型抗癌药物的功效和作用机制的关键数据，这些药物通过多种途径发挥作用，包括对 microRNA 及其相关基因转录物的直接影响。公共健康相关性：该实验室最近的研究发现了两类结构化合物，它们可诱导癌症中 Sp 蛋白抑制并抑制癌细胞生长和存活，这些化合物包括三萜类桦木酸 (BA) 和甲基 2-氰基-3,11。 -dioxo-18¿ -olean-1,12-dien-30-oate (CDODA-Me) 和 NSAID 托芬那酸 (TA) 本项目提出的研究将重点关注这些抗癌药物的作用机制，重点是它们对癌症的影响。致癌性 microRNA-27a (miR-27a) 和其他 miR 以及在抑制 Sp 蛋白和其他关键基因中的作用。