Our long-term goal is to understand mechanisms of tumor progression and metastasis and to develop new approaches for molecularly targeted therapeutics. Metastasis, a multi-step process in which primary tumor cells disseminate to distant sites of the body and form secondary tumors, is the leading cause of cancer deaths and remains one of the most poorly understood pathological processes. New biomarkers of metastatic diseases and useful targets for therapeutic intervention, including proteins, microRNAs, and other non-coding RNAs, continue to be highly sought. We and others have demonstrated the existence of metastasis-promoting and metastasis-suppressing microRNAs. Moreover, we provided proof-of-concept evidence that antagomirs targeting a pro-metastatic microRNA can be efficiently delivered to fast growing tumor cells in vivo and can block metastasis formation by otherwise highly malignant cells. The molecular mechanisms by which these individual microRNAs function in metastatic progression warrant further investigation. In this application: 1) we will identify and characterize the functional targets of metastasis-promoting microRNAs. Combining high- throughput RNA sequencing, computational approach, functional experiments, mechanistic analysis, and patient studies, we will investigate a microRNA target that represents a novel suppressor of metastasis. 2) We will study how two distinct metastasis-regulating microRNAs are connected. Our preliminary data demonstrated that expression of a specific metastasis-promoting microRNA (miR-9) leads to downregulation of the primary transcript but upregulation of the mature form of another pro-metastatic microRNA (miR-10b). Subsequently, we will investigate the mechanisms by which miR-9 regulates miR-10b biogenesis and determine whether miR-10b is required for mediating miR-9-induced metastasis. 3) We will identify and characterize new epithelial-mesenchymal transition (EMT)-regulating microRNAs. By conducting microRNA expression profiling analysis of cells that have undergone EMT, we have recently identified a microRNA signature of EMT, and discovered that two microRNAs in this signature function as EMT inducers. We will determine the mechanisms by which these two microRNAs induce EMT and whether they regulate tumor metastasis and stem cell properties. The knowledge gained from these studies will fundamentally advance our current understanding of how microRNAs and their targets regulate metastasis and EMT and may have important clinical implications.

Public Health Relevance

MicroRNAs are beginning to be implicated in tumor progression and metastasis, and they act by suppressing the expression of target genes. In this grant application, we will study the regulation of tumor metastasis and epithelial-mesenchymal transition by specific microRNAs and their target genes. These studies will reveal the molecular mechanisms underlying malignant progression and new targets for therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Jhappan, Chamelli
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
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Zhang, Peijing; Xiao, Zhenna; Wang, Shouyu et al. (2018) ZRANB1 Is an EZH2 Deubiquitinase and a Potential Therapeutic Target in Breast Cancer. Cell Rep 23:823-837
Kim, Jongchan; Piao, Hai-Long; Kim, Beom-Jun et al. (2018) Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet 50:1705-1715
Kim, Jongchan; Alavi Naini, Fatemeh; Sun, Yutong et al. (2018) Ubiquitin-specific peptidase 2a (USP2a) deubiquitinates and stabilizes ?-catenin. Am J Cancer Res 8:1823-1836
Yao, Fan; Zhou, Zhicheng; Kim, Jongchan et al. (2018) SKP2- and OTUD1-regulated non-proteolytic ubiquitination of YAP promotes YAP nuclear localization and activity. Nat Commun 9:2269
Kim, Jongchan; Yao, Fan; Xiao, Zhenna et al. (2018) MicroRNAs and metastasis: small RNAs play big roles. Cancer Metastasis Rev 37:5-15
Yuan, T; Yang, Y; Chen, J et al. (2017) Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD. Leukemia 31:2355-2364
Kim, Jongchan; Siverly, Ashley N; Chen, Dahu et al. (2016) Ablation of miR-10b Suppresses Oncogene-Induced Mammary Tumorigenesis and Metastasis and Reactivates Tumor-Suppressive Pathways. Cancer Res 76:6424-6435
Xiao, Zhenna; Zhang, Peijing; Ma, Li (2016) The role of deubiquitinases in breast cancer. Cancer Metastasis Rev 35:589-600
Zhang, Peijing; Sun, Yutong; Ma, Li (2015) ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle 14:481-7
Sun, Yutong; Ma, Li (2015) The emerging molecular machinery and therapeutic targets of metastasis. Trends Pharmacol Sci 36:349-59

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