Fine control of Wnt signaling is essential for various cellular and developmental processes. However, deregulated Wnt signaling leads to colorectal cancer (CRC). Thus, elucidating the regulatory mechanisms of Wnt signaling to allow for its targeted manipulation is critical in CRC treatment. Our long-term goal is (i) to unravel distinct molecular mechanisms that promote intestinal tumorigenesis and (ii) to develop therapeutic methods to counter CRC cell proliferation and metastasis. Previous Studies - In addition to our consistent interest in Wnt signaling in cancer and development, we recently revealed that PCNA-associated factor (PAF) hyperactivates Wnt signaling and promotes CRC cell proliferation, strongly implies that PAF promotes intestinal tumorigenesis. Despite biologic functions of PAF in controlling DNA repair and Wnt signaling, pathologic roles of PAF in cancer are undetermined. Significance - With efforts by biotechnology groups have produced only limited success to date, there is a critical need to develop novel approaches to block the Wnt pathway. One complication is that Wnt signaling is indispensable to tissue homeostasis and regeneration. Thus, the targeting of Wnt signaling regulators whose expression is specifically restricted to cancer provides an opportunity to minimize normal tissue damage. Importantly, PAF expression is significantly elevated in CRC, but not in normal tissues. Additionally, PAF knockout (KO) mice are viable. These evidences indicate potential therapeutic advantages of specifically inhibiting Wnt signaling through manipulating PAF, a Wnt signaling regulator we identified. Thus, our proposed study is necessary to determine whether PAF is a therapeutic target for CRC. Based on our previous studies and preliminary results, we hypothesize that PAF accelerates intestinal tumorigenesis via Wnt signaling and epigenetic gene regulation. To test our hypothesis, we will accomplish the following specific aims:
Aim 1 to determine in vivo tumorigenic role of PAF, using our genetically engineered mouse models;
Aim 2 to dissect PAF-mediated silencing mechanism of Wnt antagonist in CRC;
Aim 3 to determine the mechanism of PAF upregulation in CRC.

Public Health Relevance

The proposed research will address how PCNA-associated factor (PAF) accelerates intestinal tumorigenesis. Due to specific expression and functions of PAF in colorectal cancer (CRC), molecular intervention of PAF is expected to specifically inhibit Wnt signaling, a key signaling in CRC, and block CRC cell proliferation. Our proposed research is relevant to public health because revealing the molecular and cellular basis of Wnt signaling deregulation will provide new insights into human CRC and will be proof of principle for potential therapeutic application.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA193297-03
Application #
9222715
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Mietz, Judy
Project Start
2015-03-09
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
$329,400
Indirect Cost
$123,525
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Kim, Moon Jong; Xia, Bo; Suh, Han Na et al. (2018) PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis. Dev Cell 44:582-596.e4
Jung, Youn-Sang; Wang, Wenqi; Jun, Sohee et al. (2018) Deregulation of CRAD-controlled cytoskeleton initiates mucinous colorectal cancer via ?-catenin. Nat Cell Biol 20:1303-1314
Jung, Youn-Sang; Jun, Sohee; Kim, Moon Jong et al. (2018) TMEM9 promotes intestinal tumorigenesis through vacuolar-ATPase-activated Wnt/?-catenin signalling. Nat Cell Biol 20:1421-1433
Suh, Han Na; Kim, Moon Jong; Jung, Youn-Sang et al. (2017) Quiescence Exit of Tert+ Stem Cells by Wnt/?-Catenin Is Indispensable for Intestinal Regeneration. Cell Rep 21:2571-2584
Jun, Sohee; Jung, Youn-Sang; Suh, Han Na et al. (2016) LIG4 mediates Wnt signalling-induced radioresistance. Nat Commun 7:10994
Wang, Xin; Jung, Youn-Sang; Jun, Sohee et al. (2016) PAF-Wnt signaling-induced cell plasticity is required for maintenance of breast cancer cell stemness. Nat Commun 7:10633
Suh, Han Na; Jun, Sohee; Oh, Ah-Young et al. (2016) Identification of KIAA1199 as a Biomarker for Pancreatic Intraepithelial Neoplasia. Sci Rep 6:38273
Jung, Youn-Sang; Jun, Sohee; Lee, Sun Hye et al. (2015) Wnt2 complements Wnt/?-catenin signaling in colorectal cancer. Oncotarget 6:37257-68