Tumorigenesis resembles abnormal embryogenesis. Like developing organs, tumors comprise a spectrum of phenotypically heterogeneous cells and may harbor stem cell-like cells commonly referred to as cancer stem cells (CSCs). Although the CSC concept is still debated and the true molecular nature and clinical significance of CSCs remain to be fully elucidated, it is undeniable that malignant tumors are immortal at the population level. One of the key unanswered biological questions of therapeutic implication is how cancer cells in general and CSCs in particular are regulated at the molecular level with respect to their self-perpetuating (immortal) tumorigenic potential, i.e., self-renewal properties. Remarkably, malignant cells share a similar gene expression profile with embryonic SC (ESCs), which express several core regulators of self-renewal and pluripotency including Nanog (also called Nanog1), a homeodomain transcription factor located on chromosome 12. We have observed that human PCa and other cancer cells do NOT express Nanog1 but rather express a retrotransposed Nanog1 homolog, called NanogP8, located on chromosome 15. Knocking down NanogP8 significantly inhibits the CSC properties in vitro and tumor regeneration of PCa and breast and colon cancer cells. In contrast, NanogP8 overexpression is sufficient to confer CSC properties, enhances tumor regeneration, and, significantly, promotes development of castration-resistant PCa or CRPC. Our recent whole-genome ChIP-Seq experiment has uncovered distinct NanogP8 DNA-binding profiles. Furthermore, newly generated NanogP8 transgenic animals develop hyperplastic lesions in the target organs. These observations, taken together, lead to our overarching hypotheses that 1) NanogP8 possesses protumorigenic activity;2) NanogP8 promotes tumor development by regulating CSC self-renewal via unique signaling pathways;and 3) NanogP8 plays a causal role in the development of CRPC. The current project tests these hypotheses, mainly, in PCa with the following three Specific Aims. 1) To test the hypothesis that NanogP8 is causally involved in the development of CRPC;2) To elucidate the cellular and molecular mechanisms of action of NanogP8;and 3) To explore the protumorigenic roles of NanogP8 using novel transgenic animal models. Impact: Accomplishment of the goals proposed herein should greatly advance our understanding of how NanogP8 regulates the immortality of CSCs and contribute to tumor development and CRPC. It will also facilitate development of mechanism-based therapeutics that specifically targets PCSCs.

Public Health Relevance

It is generally unclear how cancer cells acquire their immortal nature. We have recently demonstrated that cancer cells appear to usurp a molecule critical for the self-renewal of embryonic stem cells (ESCs) to help achieve their immortality. Specifically, ESCs express a protein called Nanog1 localized on chromosome 12 for their self-renewal. By contrast, cancer cells preferentially express a retrotransposed homolog of Nanog1 called NanogP8, which is localized on chromosome 15 and is required for the tumorigenic potential of cancer cells. In this project, we aim to further elucidate the molecular functions and mechanisms of NanogP8 in cancer (mainly prostate cancer) cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA155693-01A1
Application #
8238435
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2012-06-01
Project End
2017-03-31
Budget Start
2012-06-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$327,850
Indirect Cost
$120,350
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
Liu, Bigang; Gong, Shuai; Li, Qiuhui et al. (2017) Transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model. Oncotarget 8:52746-52760
Rycaj, Kiera; Tang, Dean G (2017) Molecular determinants of prostate cancer metastasis. Oncotarget 8:88211-88231
Rycaj, Kiera; Li, Hangwen; Zhou, Jianjun et al. (2017) Cellular determinants and microenvironmental regulation of prostate cancer metastasis. Semin Cancer Biol 44:83-97
Liu, Bigang; Gong, Shuai; Li, Qiuhui et al. (2017) Transgenic overexpression of NanogP8 in the mouse prostate is insufficient to initiate tumorigenesis but weakly promotes tumor development in the Hi-Myc mouse model. Oncotarget :
Jeter, Collene R; Liu, Bigang; Lu, Yue et al. (2016) NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1 signaling axis. Cell Discov 2:16041
Rycaj, Kiera; Cho, Eun Jeong; Liu, Xin et al. (2016) Longitudinal tracking of subpopulation dynamics and molecular changes during LNCaP cell castration and identification of inhibitors that could target the PSA-/lo castration-resistant cells. Oncotarget 7:14220-40
Zhang, Dingxiao; Park, Daechan; Zhong, Yi et al. (2016) Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer. Nat Commun 7:10798
Liu, Ruifang; Liu, Can; Zhang, Dingxiao et al. (2016) miR-199a-3p targets stemness-related and mitogenic signaling pathways to suppress the expansion and tumorigenic capabilities of prostate cancer stem cells. Oncotarget 7:56628-56642
Chen, Xin; Li, Qiuhui; Liu, Xin et al. (2016) Defining a Population of Stem-like Human Prostate Cancer Cells That Can Generate and Propagate Castration-Resistant Prostate Cancer. Clin Cancer Res 22:4505-16
Gong, Shuai; Li, Qiuhui; Jeter, Collene R et al. (2015) Regulation of NANOG in cancer cells. Mol Carcinog 54:679-87

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