? ? Uroguanylin (UG) and guanylin (GN) are peptide hormones produced in the lumen of the GI tract where they bind to Guanylate Cyclase C (GC-C), resulting in enhanced production of cyclic guanosine monophosphate (cGMP) and activation of cystic fibrosis transmembrane conductance regulator (CFTR). We had earlier reported that UG expression is dramatically suppressed in human biopsies of colon polyps and in tumor tissues, and that this deficiency might be one of the reasons for colon carcinogenesis. Importantly, UG treatment inhibited proliferation and induced apoptosis in colon carcinoma cells. Furthermore, the oral administration of UG inhibited not only polyp formation but also their progression to intestinal tumors in Apc Min/+ mice. Subsequently, we identified an analog of UG, named SP304, which is superior to UG in potency and in other physiochemical properties. Recently, we also demonstrated that treatment with SP304 ameliorated GI inflammation in DSS- and TNBS- induced colitis models. These experiments also indicated that SP304 treatment not only suppressed expression of IL-4, IL-5, IL-23 and TNF, but also enhanced expression of IL-10 in inflamed tissues from TNBS-treated mice, suggesting that the anti-inflammatory activity of SP304 might be via the downregulation of pro-inflammatory cytokines. Therefore, this grant proposal is to examine the effect of SP304 treatment in DSS-induced colorectal cancer (CRC) development in Apc min/+ mice and spontaneous development of colitis-induced CRC in IL-10 knock out mice. These mice models are widely used for colitis-induced CRC. We will also examine levels of UG and pro-inflammatory cytokines to assess their association with colitis- induced CRC. Successful completion of the proposed research would have examined the potentials of SP304 in prevention and control of CRC in IBD patients. PUCLIC
UG and GN are peptide hormones that bind to GC-C and stimulate production of cGMP in epithelial cells lining the GI mucosa. Subsequent activation of CFTR and the downstream signaling pathways regulate the balance between proliferative and apoptotic rates in the GI mucosa. We had earlier reported that UG expression is dramatically suppressed in human biopsies of colon polyps and tumor tissues, and that this deficiency might be one of the reasons for colon carcinogenesis. Moreover, oral administration of UG inhibited not only polyp formation but also their progression to intestinal tumors in Apc Min/+ mice. More importantly, treatment with SP304, an analog of UG, also ameliorated GI inflammation in DSS- and TNBS-induced colitis models, possibly via suppression of pro-inflammatory cytokines. Therefore, this grant proposal is to examine the effect of SP304 treatment in animal models of colitis-induced colorectal cancer (CRC) and to explore mechanism of action of SP304. ? ? ?
|Chang, Wen-Chi L; Masih, Shet; Thadi, Anusha et al. (2017) Plecanatide-mediated activation of guanylate cyclase-C suppresses inflammation-induced colorectal carcinogenesis in Apc+/Min-FCCCmice. World J Gastrointest Pharmacol Ther 8:47-59|