Mounting evidence indicates that various human tumors contain populations of stem-like cancer cells, often termed cancer stem cells (CSCs) or tumor-initiating cells. Our lab, in the past few years, has focused on identification and functional characterizations of such tumorigenic cells in human prostate cancer (PCa). Our results have clearly demonstrated that PCa cells are organized as a tumorigenic hierarchy that contains subsets of relatively quiescent stemlike cancer cells, abundant and actively proliferating tumor progenitors, and the bulk differentiated PCa cells. Of significance, we have observed that the CD44+ PCa cell population contains both CSCs and tumor progenitors (i.e., PCa stem/progenitor cells). Recently, we have directed our efforts to understanding how PCa stem/progenitor cells are regulated and how regulatory molecules impact PCa development in vivo. In one project, for example, we have shown that Nanog, critical for ES cell selfrenewal and pluripotency, also plays an essential role in regulating PCa stem/progenitor cell properties and development of prostate (and other) cancers. In the current project, we show that a microRNA, miR-34a, plays a critical negative role in PCa stem/progenitor cells as well as PCa development. Importantly, preliminary data suggest that miR-34a exerts its negative impact on PCa stem/progenitor cells via targeting CD44 and Nanog. Based on our preliminary observations, we propose, in this R21 application, two Specific Aims: 1) to further study the role of miR-34a in regulating PCa stem/progenitor cells and tumor development;and 2) to test the hypothesis that CD44 and Nanog represent two critical downstream targets of miR-34a in PCa stem/progenitor cells.
These aims will be accomplished by a spectrum of cell biological and molecular approaches combined with in vivo tumor experiments. The accomplishment of these goals will greatly advance our understanding of PCa stem/progenitor cell regulation and lay a solid foundation for developing novel anti-PCa therapeutics.

Public Health Relevance

Prostate cancer (PCa) is the number one malignancy that inflicts and second leading cancer that kills American men. Increasing evidence suggests that PCa, like many other solid tumors, is fuelled by stem-like cells called cancer stem cells. In this project, we show that a microRNA, miR-34a, negatively regulates PCa stem/progenitor cells and potently inhibits PCa development. Importantly, miR-34a demonstrates potential therapeutic potential against PCa metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA150009-02
Application #
8117545
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Jhappan, Chamelli
Project Start
2010-09-01
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
2
Fiscal Year
2011
Total Cost
$200,004
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Yang, Tao; Rycaj, Kiera; Liu, Zhong-Min et al. (2014) Cancer stem cells: constantly evolving and functionally heterogeneous therapeutic targets. Cancer Res 74:2922-7
Gogada, Raghu; Yadav, Neelu; Liu, Junwei et al. (2013) Bim, a proapoptotic protein, up-regulated via transcription factor E2F1-dependent mechanism, functions as a prosurvival molecule in cancer. J Biol Chem 288:368-81
Badeaux, Mark A; Jeter, Collene R; Gong, Shuai et al. (2013) In vivo functional studies of tumor-specific retrogene NanogP8 in transgenic animals. Cell Cycle 12:2395-408
Qin, Jichao; Liu, Xin; Laffin, Brian et al. (2012) The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell 10:556-69
Liu, Can; Kelnar, Kevin; Vlassov, Alexander V et al. (2012) Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor-suppressive functions of let-7. Cancer Res 72:3393-404
Tang, Dean G (2012) Understanding cancer stem cell heterogeneity and plasticity. Cell Res 22:457-72
Yan, Hong; Chen, Xin; Zhang, Qiuping et al. (2011) Drug-tolerant cancer cells show reduced tumor-initiating capacity: depletion of CD44 cells and evidence for epigenetic mechanisms. PLoS One 6:e24397
Liu, Can; Kelnar, Kevin; Liu, Bigang et al. (2011) The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 17:211-5
Jeter, C R; Liu, B; Liu, X et al. (2011) NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene 30:3833-45
Liu, Can; Tang, Dean G (2011) MicroRNA regulation of cancer stem cells. Cancer Res 71:5950-4

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