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; 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（由适用提供）：结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。结肠癌化学疗法依赖于多种细胞毒性药物，靶向剂及其组合，并且越来越需要开发针对旨在抑制肿瘤生长，进展和转移并诱导凋亡的特定途径的替代药物。特异性蛋白（SP）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所需的基因表达（P27抑制），存活率（Survivin）和血管生成（VEGF，VEGF，VEGFR1和VEGFR2）。该实验室中的研究现已表明，tolfenamic酸（TA）和β酸（BA）和一种新型的合成三萜酸（酯），即甲基-2-氰基-3,11-Dioxo-18。-orean-1,12-Dien-1,12-Dien-30-oate（CDODA-ME）诱导G2/M蛋白酶的蛋白酶蛋白酶的蛋白酶蛋白酶蛋白酶。这些作用与化合物诱导的致癌microRNA-27A（miR-27a）和其他miR的表达的调节直接相关。因此，我们假设TA，BA和CDODA-ME代表了针对miR-27a和其他miR的独特抗癌剂。拟议的研究将表征结肠癌中药物相互作用引起的作用和作用机制。 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，以及它们随后对SP依赖性基因的下游调节，生长抑制，抗基因和抗抑制性反应。 TA，BA和CDODA-ME还降低了结肠癌细胞中其他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。 AIM 3将研究小鼠元素的TA，BA和CDODA-ME的体内抗癌活性和结肠癌的“ Min”模型，并确定化合物-MIR相互作用。此外，已经开发出过表达miR-27a的小鼠是研究这种致癌miR在结肠癌发生中的作用的问题。这些研究将提供有关TA，BA和CDODA-ME的有效性和作用机理的关键数据，作为一类新型的抗癌药物，这些药物通过多种途径起作用，包括直接对MicroRNA及其相关基因转录物的直接影响。公共卫生相关性：该实验室的最新研究确定了两种结构性类别的化合物，它们在癌症中诱导SP蛋白表达并抑制癌细胞的生长和生存。这些化合物包括三萜类β-苯甲酸（BA）和甲基2-Cyano-3,11-dioxo-18¿-orean-1,12-dien-30-oate（CDODA-ME）和NSAID TOLFENAMIC（TA）。该项目中提出的研究将重点关注这些抗癌药的作用机理，重点是它们对致癌性microRNA-27A（miR-27a）和其他miR的作用以及其他miR的作用，以及在SP蛋白和其他关键基因表达中的作用。