The primary objective of this proposal is to elucidate new mechanisms by which themultifunctional cytokine TGF- affects tumor metastasis. TGF- plays important roles incontrolling many types of cellular functions in the regulation of development and homeostasis.During tumorigenesis, TGF- is known to inhibit tumor formation in the early stage, but act as apotent promoter for late stages of the process, including metastasis. While the framework ofthe primary signaling pathway through which TGF- acts to regulate a wide range of biologicalprocesses has been established, the mechanisms by which TGF- functions to determinespecific outcomes of those biological processes remain to be fully explored. Many microRNAs(miRNAs) are found to be down-regulated in cancer cells, leading to the up-regulation of theirtarget genes to affect tumorigenesis. We intend to test the hypothesis that specific miRNAs aremediators of TGF- to regulate various cellular functions in the context of tumor metastasis. Inpreliminary studies, we found that the expression level of a set of miRNAs in breast and livercancers was decreased upon treatment of TGF- . Among them, miR-34a and miR-126 werechosen for further analyses because of their putative target genes, CCL22 and SDF1, areinvolved in the recruitment of regulatory T cells (Treg) and mesenchymal stem cells (MSCs),respectively. Based on those results, we further hypothesize that TGF- enhances tumormetastasis by changing the tumor microenvironment through two new mechanisms: theinhibition of immune function via the repression of miR-34a to induce the production of CCL22,which in turn stimulates the accumulation of Treg cells in the areas where metastaticcolonization occurs, and recruitment of MSCs to support the growth of metastatic cells. Wepropose two aims to test our hypothesis, determining the functions of miR-34a and miR-126 asmediators of TGF- to affect metastasis in vitro and in vivo, and elucidating the mechanism bywhich TGF- regulates the expression/processing of these miRNAs. Ultimately,characterization of these novel mechanisms by which TGF- promotes metastasis will providepotential new targets for metastatic cancer therapy.

Public Health Relevance

As a critical cytokine regulating many cellular activities, TGF-ss is involved in the pathological processes of many types of human diseases, such as autoimmune disease, cancer, and fibrosis. A better understanding of the mechanisms associated with TGF-ss action in various cell/tissue types, will help the development of better therapies for those diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151541-02
Application #
8082679
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
2010-06-07
Project End
2015-04-30
Budget Start
2011-07-13
Budget End
2012-04-30
Support Year
2
Fiscal Year
2011
Total Cost
$311,849
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Markowitz, Geoffrey J; Yang, Pengyuan; Fu, Jing et al. (2016) Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes. Cancer Res 76:2394-405
Xu, Xin; Zhang, Yun; Jasper, Jeff et al. (2016) MiR-148a functions to suppress metastasis and serves as a prognostic indicator in triple-negative breast cancer. Oncotarget 7:20381-94
Markowitz, Geoffrey J; Michelotti, Gregory A; Diehl, Anna Mae et al. (2015) Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma. Sci Bull (Beijing) 60:762-772
Zhang, Yun; Wang, Xiao-Fan (2014) Post-transcriptional regulation of MTA family by microRNAs in the context of cancer. Cancer Metastasis Rev 33:1011-6
Yang, Pengyuan; Markowitz, Geoffrey J; Wang, Xiao-Fan (2014) The hepatitis B virus-associated tumor microenvironment in hepatocellular carcinoma. Natl Sci Rev 1:396-412
Zhang, Yun; Yang, Pengyuan; Wang, Xiao-Fan (2014) Microenvironmental regulation of cancer metastasis by miRNAs. Trends Cell Biol 24:153-60
Guo, Xing; Wang, Xiao-Fan (2013) A P(E)RM(I)T for BMP signaling. Mol Cell 51:1-2
Zhang, Yun; Yang, Pengyuan; Sun, Tao et al. (2013) miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis. Nat Cell Biol 15:284-94
Curtis, Valerie F; Wang, Hui; Yang, Pengyuan et al. (2013) A PK2/Bv8/PROK2 antagonist suppresses tumorigenic processes by inhibiting angiogenesis in glioma and blocking myeloid cell infiltration in pancreatic cancer. PLoS One 8:e54916
Yong, Sheila T; Wang, Xiao-Fan (2012) A novel, non-apoptotic role for Scythe/BAT3: a functional switch between the pro- and anti-proliferative roles of p21 during the cell cycle. PLoS One 7:e38085

Showing the most recent 10 out of 13 publications