MicroRNAs as Targets for Colon Cancer Chemotherapy

MicroRNA 作为结肠癌化疗的靶点

• 批准号: 7563104
• 负责人: Stephen H. Safe
• 金额: $ 23.74万
• 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/7563104
• 关键词: Accounting; Acids; Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Betulinic Acid; Cancer Cell Growth; Cancer Patient; Cause of Death; Chemopreventive Agent; Chemotherapy-Oncologic Procedure; Colon Carcinoma; Colorectal Cancer; Curative Surgery; Cytotoxic agent; Data; Developed Countries; Developing Countries; Development; Diagnosis; Diet; Disease; Drug Delivery Systems; Environmental Risk Factor; Esters; Gene Expression; Genes; Genetic Markers; Genetic Predisposition to Disease; Growth; Incidence; Inherited; Laboratories; Link; Localized Disease; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; MicroRNAs; Modeling; Molecular Genetics; Mus; Mutation; Neoplasm Metastasis; Nomads; Non-Steroidal Anti-Inflammatory Agents; Oncogenic; Other Genetics; Pancreas; 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; Vascular Endothelial Growth Factors; Xenograft procedure; angiogenesis; cancer cell; colon carcinogenesis; experience; in vivo; multicatalytic endopeptidase complex; novel; overexpression; public health relevance; response; survivin; transcription factor; tumor; tumor growth

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死亡原因之一。结肠癌化疗依赖于多种细胞毒性药物、靶向药物及其联合治疗，越来越需要开发针对抑制肿瘤生长、进展和转移以及诱导细胞凋亡的特定途径的替代药物。特异性蛋白（Sps）是在许多肿瘤中过表达的转录因子，Sps调节癌细胞和肿瘤生长（p27抑制）、生存（survivin）和血管生成（VEGF、VEGFR1和VEGFR2）所需基因的表达。本实验室的研究现已表明，甲苯胺酸（TA）和白木酸（BA）以及一种新型合成的三萜酸（酯），即甲基-2-氰-3,11-二氧氧-18¿-olean-1,12-二烯-30-oate （CDODA-Me）可诱导结肠癌细胞中G2/M生长停滞和蛋白酶体不依赖Sp蛋白的降解。这些作用与化合物诱导的致癌microRNA-27a （mir-27a）和其他miRs表达的调节直接相关。因此，我们假设TA、BA和CDODA-Me代表了一类独特的靶向miR-27a和其他mir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。Aim 1将重点关注TA-/BA-/CDODA-Me-miR-27a相互作用，并研究mir -27a依赖性ZBTB10和Myt-1表达的激活及其随后对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。TA、BA和CDODA-Me也会降低结肠癌细胞中其他miRs的表达，这些miRs包括miR-23a和miR-24-2，它们与miR-27a形成集群。目的2将研究TA-、BA-和CDODA-Me-miR（23a~24-2）的相互作用，并确定它们在介导这些化合物的抗癌活性中的作用。目的3将研究TA、BA和CDODA-Me在小鼠移植瘤和结肠癌“Min”模型中的体内抗癌活性，并确定化合物与mir的相互作用。此外，研究人员还开发了过表达miR-27a的小鼠作为探针，研究这种致癌miR在结肠癌发生中的作用。这些研究将为TA， BA和CDODA-Me作为一类新型抗癌药物的功效和作用机制提供关键数据，这些药物通过多种途径起作用，包括直接作用于microrna及其相关基因转录物。公共卫生相关性：该实验室最近的研究已经确定了两种结构类型的化合物，它们在癌症中诱导Sp蛋白抑制并抑制癌细胞的生长和存活。这些化合物包括三萜白桦酸（BA）和甲基2-氰基-3,11-二氧基-18¿-齐奥烯-1,12-二烯-30-oate （CDODA-Me）和非甾体抗炎药甲苯胺酸（TA）。本项目拟重点研究这些抗癌药物的作用机制，重点研究其对致癌microRNA-27a （miR-27a）等miRs的作用，以及对Sp蛋白等关键基因的抑制作用。