Pharm.D. (six years)
Biomedical and Pharmaceutical Sciences
cancer; liver receptor homolog 1; colon cancer; pancreatic cancer; signaling pathway
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LRH1 as a driving factor for cancer development
Alissa Margraf, Qi Tang, Qiushi Lin, Xiaoqun Dong
Department of Biomedical and Pharmaceutical Science, College of Pharmacy, The University of Rhode Island, Pharmacy Building, 7 Greenhouse Road, Kingston, RI 02881 USA
Cancer is a major public health problem worldwide. Colon cancer ranks as the third most common causes of cancer mortality in the United States, with an estimated 96,830 new cases and 50,310 deaths in 2014. Colon cancer develops in the digestive tract where benign growths called polyps transform into malignant tumors. Colon cancer cells invade and destroy nearby tissue and can even migrate, forming new metastatic tumors in other parts of the body. However, the molecular mechanism of colon tumorigenesis is poorly understood and the prognosis is very bad due to multiple drug resistance. Therefore, there is urgent need to identify a novel therapeutic target for colon cancer treatment. This application focuses on gaps in knowledge regarding the cellular pathogenesis in an attempt to identify new molecular targets for therapy of this serious disease.
Recently, LRH1 (liver receptor homolog 1), an orphan nuclear receptor, has been identified as a key regulator for intestinal function with implications to common intestinal diseases including colorectal cancer. Research shows that LRH1 can induce cell proliferation through promoting the cell cycle progression by the induction of proteins cyclin D1 and E1 in the intestine. This action is mediated by Wnt/β-catenin/Tcf4 signaling pathway. Through investigations on the role of LRH1 in the pancreas, we have observed overexpression of LRH1 correlated with reduced survival and more aggressive phenotype of pancreatic cancer patients. Because the pancreas, liver and intestine (colon and rectum) are derived from a common precursor during embryonic development and differentiation, LRH1 may be a central signaling molecule during the development and progression of colon cancer. In this regard, LRH1 overexpression is proposed to sensitize mucosa cells, lining the inside of the colon, to genomic alterations-driven malignant formation and progression. The oncogenic role of LRH1 has been demonstrated by up-regulating the expression of markers of cancer stem cells, enhancing sphere formation, as well as promoting tumor formation, angiogenesis and liver metastasis in pancreatic cancer. We hypothesize that overexpressed LRH1 also promotes colon tumorigenesis by initiating cancer stem cells formation. Because these cells originate from the same progenitor cell type and share similar characteristics, it is reasonable to incorporate recent studies on LRH1 in pancreatic cancer to the current application with the tumorigenesis of colon cancer.
New findings will link the dysfunction of colon development/differentiation signaling pathways with tumorigenesis by clarifying the crosstalk between LRH1 and cancer stem cell initiation. If successful, the information gained from this study has important clinical implications for pancreatic, liver, colon and other cancers with dysregulated LRH1 network. The project will provide foundation for future development of novel therapies targeting LRH1-related signaling pathways in pancreatic, liver and colon cancer, which will translate our basic scientific discovery (from bench to bedside) to pre-clinical trials to treat cancer patients.