Department of biochemistry and Molecular biology
Raymond DuBois, MD, PhD
Office (CSB-601): 843-792-2081
Lab (DDB-321): 843-876-2270
Research in the DuBois’ laboratory is focused on understanding the molecular, genetic, and cellular basis for colorectal cancer (CRC). As a part of these efforts, my laboratory has had long-standing thematic interests in exploring the effects of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, on CRC prevention. Understanding the molecular mechanisms involved in the anti-tumor effects of aspirin on CRC would be a tremendous advance alone. The compelling evidence indicates that the anti-tumor effect of NSAIDs, in part, are due to reduction of pro-inflammatory prostaglandin E2 (PGE2) production via inhibiting enzymatic activity of cyclooxygenases (COX-1 and COX-2). My laboratory has focused on elucidating the mechanisms underlying the role of COX-2 and COX-2-derived PGE2 in CRC initiation, growth, progression, and metastasis. Our progress has led to many milestones in CRC prevention and treatment. My research continues to hold promise for the development of more effective prevention and treatment strategies for CRC.
One major area of interest is to understand how PGE2 promotes CRC formation, progression, and metastasis. My early work has demonstrated that PGE2 promotes tumor growth and progression by induction of tumor epithelial cell proliferation, survival, and migration/invasion via multiple signaling pathways. Recently, our novel findings showed that PGE2 promotes CRC initiation, growth, and metastasis by silencing certain tumor suppressor and DNA repair genes via DNA methylation and by inducting cancer stem cell formation and expansion. A selective COX-2 inhibitor or an EP4 antagonist suppresses colonic cancer stem cell expansion and liver metastasis. In another focus area, we are investigating how chronic inflammation contributes to CRC initiation, progression, and metastasis. One of our recent projects revealed for the first time that a chemokine receptor, CXCR2, is required for infiltration of myeloid-derived suppressor cells (MDSCs) from the circulatory system to inflamed colonic mucosa and colitis-associated tumors in vivo. We further demonstrated that CXCR2-expressing MDSCs contribute to chronic inflammation in the colon via Th17 cells and promote colitis-associated tumor formation, growth, and progression via suppression of colonic CD8+ T cell cytotoxic activity. Our findings not only demonstrate that CXCR2 is one of the mediators connecting inflammation and CRC, but also provides a rationale for development of new therapeutic approaches to subvert chronic inflammation-induced and/or tumor-induced immunosuppression by using CXCR2 antagonists and/or neutralizing antibodies. Moreover, we found a novel role of a nuclear receptor, PPARd, in connecting chronic inflammation and tumorgenesis. Our findings not only reveal novel functions of PPARd in colonic inflammation and tumorigenesis, but also provides a rationale for development of PPARd antagonists as new therapeutic agents in treatment of IBD and CRC.
Recent Publications | Additional Publications
Wang D, Sun H, Wei J, Cen B, DuBois RN. (2017) CXCL1 is critical for premetastatic niche formation and metastasis in colorectal cancer. Cancer Res 77(13):3655-3665.
Kim SH, Park YY, Cho SN, Margalit O, Wang D, DuBois RN. (2016) Kruppel-like factor 12 promotes colorectal cancer growth through early growth response protein 1. PloS One 11:e0159899.
Wang D, Fu L, Sun H, Guo L, DuBois RN. (2015) Prostaglandin E2 promotes colorectal cancer stem cell expansion and metastasis in mice. Gastroenterology 149:1884-95 e4.
Wang D, Fu L, Ning W, Guo L, Sun X, Dey SK, et al. (2014) Peroxisome proliferator-activated receptor delta promotes colonic inflammation and tumor growth. Proc Natl Acad Sci USA 111:7084-9.
Kim SH, Margalit O, Katoh H, Wang D, Wu H, Xia D, et al. (2014) CG100649, a novel COX-2 inhibitor, inhibits colorectal adenoma and carcinoma growth in mouse models. Investigational New Drugs 32:1105-12.
Katoh H, Wang D, Daikoku T, Sun H, Dey SK, Dubois RN. (2013) CXCR2-expressing myeloid-derived suppressor cells are essential to promote colitis-associated tumorigenesis. Cancer Cell 24:631-44.
Kim SH, Wang D, Park YY, Katoh H, Margalit O, Sheffer M, et al. (2013) HIG2 promotes colorectal cancer progression via hypoxia-dependent and independent pathways. Cancer Lett 341:159-65.
Wang D, Ning W, Xie D, Guo L, DuBois RN. (2012) Peroxisome proliferator-activated receptor delta confers resistance to peroxisome proliferator-activated receptor gamma-induced apoptosis in colorectal cancer cells. Oncogene 31:1013-23.
Xia D, Wang D, Kim SH, Katoh H, DuBois RN. (2012) Prostaglandin E2 promotes intestinal tumor growth via DNA methylation. Nat Med 18:224-6.
Kim SH, Park YY, Kim SW, Lee JS, Wang D, DuBois RN. (2011) ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression. Cancer Res 71:7010-20.
Wang D, DuBois RN. Eicosanoids and cancer. (2010) Nat Rev Cancer 10:181-93.