Abstract 3165: Galectin-4, a key regulator of inflammation and cancer of the intestine

The inflammatory bowel diseases including ulcerative colitis and Crohn9s disease are chronic inflammatory disorders of the intestine. It is well recognized that a serious long-term complication of chronic inflammation is the development of colorectal cancer (CRC). Although various mechanisms underlying different chronic inflammation conditions are known, it is increasing clear that proinflammatory cytokines produced during immune responses are the key contributing factors to the above disease states. On the other hand, genetic alterations inducing CRC also promote inflammatory responses in the gastrointestinal microenvironment. This interdependent relationship between oncogenesis and inflammation suggests that it is possible to identify a regulatory molecule that links these two cellular processes. The long-term interest of our efforts is to determine the mechanisms of galectin-4 (gal-4) in the normal and disease physiology of the human gastrointestinal tract. Gal-4 is expressed predominantly by the gastrointestinal epithelia. It is secreted and binds to specific oligosaccharide moiety in glycoproteins on the cell surface. We have recently demonstrated that gal-4 down-regulates cell proliferation and its loss of expression coincides with CRC onset and progression, and suggested that gal-4 functions as a tumor suppressor. The purpose of this study is to determine whether gal-4 regulates inflammatory responses in colorectal cells. In this study, we used gal-4 +ve CRC cells, HT-29 and LS-180 and neutralized their surface-bound gal-4 with gal-4 antibodies. Such cells proliferated profusely with concomitant up-regulation of transcription of 47 genes of which 17 are known partners/gene targets of multiple inflammation signaling pathways. Extracellular (spent) media obtained from these experiments were found to contain unique cytokines that are known to be pro-tumorigenic. In converse experiments, exposure of gal-4 -ve HCT116 cells to purified gal-4 resulted in decreased cell proliferation. Concomitantly, there was increased expression of p27, decreased expressions of cyclin D1 and c-Myc. These data suggested that binding of gal-4 to cell surface arrests cell cycle. Finally, analysis of rat colon tissue sections obtained from dextran sulfate-sodium (DSS) induced chronic colitis (kindly given by Dr. Daniel W. Rosenberg, Univ. of Connecticut CT) suggested that the epithelial cells at the colitis regions exhibited loss of gal-4 expression. These data together suggested that surface gal-4 down-regulates inflammatory response pathways, cell proliferation and oncogenic events. These data also suggested that gal-4 protein therapy and re-expression of gal-4 in lesions of chronic inflammation and CRC are potentially attractive methods of controlling these diseases. *A part of this study was carried out by the authors while working at the Texas Tech University Health Sciences Center Note: This abstract was not presented at the meeting. Citation Format: U.S. Rao, Prema S. Rao. Galectin-4, a key regulator of inflammation and cancer of the intestine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3165. doi:10.1158/1538-7445.AM2015-3165