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Roles of miR-129 in colorecal cancer

miR-129 在结直肠癌中的作用

基本信息

批准号：
9105488
负责人：
JINGFANG JU
金额：
$ 35.92万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-04 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105488
关键词：
Acute Apoptosis Apoptotic Azoxymethane Binding CD44 gene Cancer Etiology Carcinogens Cell Cycle Cell Cycle Regulation Cell Death Cell Line Cells Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Coupled Development Dextran Sulfate Disease Progression Ectopic Expression Epigenetic Process Epithelial Cells Event Failure Fluorouracil Gene Expression Genes Genotoxic Stress HCT116 Cells Human In Vitro Investigation Knockout Mice Knowledge Lead Leucovorin Liquid Chromatography Liver Malignant Neoplasms Mediating Messenger RNA Methylation MicroRNAs Mission Modeling Molecular Mus National Cancer Institute Neoplasm Metastasis Operative Surgical Procedures Organoids Pathway interactions Patients Primary Neoplasm Proteins Proteomics Regulator Genes Resistance Role SW480 SW620 Specimen Spectrometry, Mass, Electrospray Ionization Staging Testing Thymidylate Synthase Tumor Biology Tumor Stem Cells Tumor Suppressor Proteins Tumor Tissue United States Universities Untranslated RNA Woman Xenograft procedure base biobank cancer cell cancer stem cell chemotherapy clinically relevant colon cancer cell line colon cancer patients colon tumorigenesis fluoropyrimidine in vivo knock-down men mortality mouse model nanoscale neoplastic cell new therapeutic target novel novel therapeutic intervention overexpression oxaliplatin promoter public health relevance resistance mechanism response subcutaneous tumor tumor microenvironment tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer is the third leading cause of cancer mortality in both men and women in the United States. Resistance to fluoropyrimidine-based (e.g. 5-fluorouracil/Oxaliplatin/Leucovorin) chemotherapy is one of the major reasons for the failure of treating advanced colorectal cancer. The lack of ability for tumor cells to undergo apoptosis after genotoxic stress is one of the key contributors to such resistant mechanism. Mounting evidence has demonstrated that non- coding microRNAs (miRNAs) are crucial regulators of gene expression, in particular, under acute genotoxic stress. However, there is still limited knowledge about the role of miRNAs in apoptosis in colorectal cancer. Our recent studies discovered a novel mechanism of miR-129 mediated apoptosis by suppressing the expression of anti-apoptotic protein Bcl2. In addition to Bcl2, miR-129 also suppresses the expression of 5-fluorouracil (5-FU) target protein thymidylate synthase (TS) and cell cycle control gene E2F3. Ectopic expression of miR-129 restored apoptosis in colon cancer cell lines by suppressing Bcl2 and sensitized colon cancer cells to 5- FU treatment both in vitro and in vivo. We further demonstrated that the loss of miR-129 expression in colorectal cancer patients is a critical event during disease progression. More importantly, we were able to reverse the chemoresistance in colon cancer stem cells with miR- 129. Based on these, it is important to further investigate the regulatory mechanism of miR-129 and its clinical relevance and impact in colorectal cancer. In the proposed project, we will test the hypothesis that miR-129 is indeed a tumor suppressor of colorectal cancer and a novel modulator of chemosensitivity to 5-FU based treatment. In Specific Aim 1, we will test the hypothesis that modulating miR-129 expression can be an effective approach to restore apoptosis, cell cycle control, and reverse chemoresistance in colon cancer stem cells. Specific Aim 2, we will test the clinical relevance of miR-129 in colorectal cancer using various colon cancer mouse models and patient specimens. Specific Aim 3, we will test the hypothesis the miR-129 is a tumor suppressor by fully understanding the mechanism of its major targets and pathways. The proposed investigation will provide further understanding of miR-129 in colorectal cancer progression and response to 5-FU based chemotherapy. It has the potential to develop novel therapeutic approaches to enhance 5-FU efficacy to benefit patients.