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Upstream Regulation and Downstream effectors of c-MYC in Ovarian Cancer

卵巢癌中c-MYC的上游调控和下游效应子

基本信息

批准号：
10203762
负责人：
Pablo Elias Vivas-Mejia
金额：
$ 33.1万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-01 至 2022-09-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203762
关键词：
Address Binding Bioinformatics Biological Biological Assay Cancer Patient Cell Death Cell Proliferation Cell Survival Cells Cessation of life Cisplatin Coupled DNA Data Data Analyses Developing Countries Development Drug resistance Female Formalin Gene Expression Genes Genetic Transcription Human Individual Liposomes Luciferases MYC gene Malignant - descriptor Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mediating Messenger RNA MicroRNAs Minority-Serving Institution Mission Modality Molecular Nodule Normal Cell Nude Mice Oligonucleotides Paraffin Embedding Pathway interactions Patients Production Promoter Regions Protein Biosynthesis Proteins Proto-Oncogene Proteins c-myc Publishing Puerto Rican RNA RNA Interference Recurrence Regulation Reporter Research Research Personnel Resistance Sampling Serous Socioeconomic Status Technology Testing The Cancer Genome Atlas Therapeutic Effect Training Transfection Tumor Weights Untranslated RNA Untranslated Regions Up-Regulation Western Blotting Woman anticancer research antitumor effect c-myc Genes cancer cell cancer health disparity cancer initiation cancer therapy cancer type chemotherapy chromatin immunoprecipitation clinically relevant data portal deep sequencing experimental study female reproductive system graduate student health disparity improved in silico insight interest minority health mouse model novel novel therapeutics overexpression programs response targeted treatment therapeutic evaluation transcription factor transcriptome sequencing translational cancer research tumor tumor growth tumor progression undergraduate student vector control

项目摘要

ABSTRACT Ovarian cancer remains an important cause of female cancer-related deaths, with approximately 22,440 new cases and about 14,080 deaths predicted for 2017. Consistent with the objective of this proposal, there is an urgent need to identify better targets for therapy against advanced and drug-resistant high-grade serous ovarian cancer (HGSOC), the most malignant and lethal of the gynecological cancers. One such possibility is c-MYC, an oncogene highly abundant in most cancers, including HGSOC. Previous studies by our research team using “The Cancer Genome Atlas” (TCGA) data portal showed that recurrence of HGSOC occurred faster for patients with higher c-MYC expression. In addition, small-interference RNA (siRNA)-mediated c-MYC silencing decreased cell proliferation and reduced tumor growth in an ovarian cancer mouse model. Together, these results suggest that c-MYC could be a clinically relevant target for HGSOC patients. Although the molecular mechanisms of c-MYC overexpression have been extensively studied in different types of cancer, the mechanism leading to c-MYC up-regulation in HGSOC have not been addressed. Preliminary results from our research team indicate that c-MYC could be regulated post-transcriptionally by microRNAs in HGSOC. MicroRNAs (miRNAs) are small non-coding RNAs that can potentially bind to thousands of different messenger RNAs and inhibit protein synthesis. By using bioinformatics and molecular studies we identified several miRNAs that potentially regulate c-MYC expression in ovarian cancer cells. Most important, transient transfection of oligonucleotide miRNA mimics for those miRNAs showed that miR-98, miR-106a and miR-18a significantly decreased the c-MYC protein levels, and reduced the cell proliferation of ovarian cancer cells. Together, our data provide insight into novel mechanisms of c-MYC regulation in HGSOC. Our overall hypothesis is that miR-98, miR-106a and miR-18a post-transcriptionally regulate c-MYC expression in HGSOC. In addition, we will test the hypothesis that c-MYC regulates key genes associated with cell survival and with the cisplatin resistance of HGSOC cells. This hypothesis will be addressed by pursuing the following Specific Aims: (1) identify the microRNAs post-transcriptionally regulating c-MYC expression in HGSOC cells; (2) investigate the biological consequences and therapeutic effects of siRNA-mediated c-MYC silencing in combination with miR-98, miR-106a or miR-18a mimics, in HGSOC; and (3) elucidate the c-MYC downstream effectors in ovarian cancer cells. Our contribution to the field of molecular mechanisms of drug resistance will be a detailed elucidation of the Upstream Regulation and Downstream Effectors of c-MYC in HGSOC. In response to one of the main missions of the “Center for Collaborative Research in Health Disparities” (RCMI), this proposal will improve the participation of researchers in minority institutions in basic and translational cancer research and will result in the training of local graduate and undergraduate students in cutting-edge technology and novel concepts in cancer research.

摘要