Roles of miR-129 in colorecal cancer

miR-129 在结直肠癌中的作用

• 批准号: 9916629
• 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
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-04 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916629
• 关键词: 3-Dimensional; Acute; Apoptosis; Apoptotic; Azoxymethane; BCL-2 Protein; 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; LGR5 gene; 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; Pathologic; Pathway interactions; Patients; Primary Neoplasm; Proteins; Proteomics; Regulator Genes; Resistance; Role; SW480; SW620; Specimen; Spectrometry, Mass, Electrospray Ionization; 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; colorectal cancer progression; 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 xenograft; tumorigenesis

 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.



项目成果

The emerging role of miR-506 in cancer.

miR-506 在癌症中的新作用

• DOI: 10.18632/oncotarget.11294
• 发表时间: 2016-09-20
• 期刊: Oncotarget
• 作者: Li J;Ju J;Ni B;Wang H
• 通讯作者: Wang H

Modified miR-15a has therapeutic potential for improving treatment of advanced stage colorectal cancer through inhibition of BCL2, BMI1, YAP1 and DCLK1.

修饰的miR-15a通过抑制BCL2，BMI1，YAP1和DCLK1具有改善晚期结直肠癌治疗的治疗潜力。

• DOI: 10.18632/oncotarget.23414
• 发表时间: 2018-01-05
• 期刊: Oncotarget
• 作者: Fesler A;Liu H;Ju J
• 通讯作者: Ju J

Development of novel miR-129 mimics with enhanced efficacy to eliminate chemoresistant colon cancer stem cells.

• DOI: 10.18632/oncotarget.22322
• 发表时间: 2018-02-06
• 期刊: Oncotarget
• 作者: Wu N;Fesler A;Liu H;Ju J
• 通讯作者: Ju J

Downregulated miR-506 expression facilitates pancreatic cancer progression and chemoresistance via SPHK1/Akt/NF-κB signaling.

下调 miR-506 表达通过 SPHK1/Akt/NF-kappa B 信号传导促进胰腺癌进展和化疗耐药

• DOI: 10.1038/onc.2016.90
• 发表时间: 2016-10-20
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Li, J.;Wu, H.;Li, W.;Yin, L.;Guo, S.;Xu, X.;Ouyang, Y.;Zhao, Z.;Liu, S.;Tian, Y.;Tian, Z.;Ju, J.;Ni, B.;Wang, H.
• 通讯作者: Wang, H.

microRNA based prognostic biomarkers in pancreatic Cancer.

• DOI: 10.1186/s40364-018-0131-1
• 发表时间: 2018
• 期刊: Biomarker research
• 影响因子: 11.1
• 作者: Guo S;Fesler A;Wang H;Ju J
• 通讯作者: Ju J