Tumor biological aspects of the mucin-like glycoprotein CD43

Abstract: Cancer cells overexpress aberrant forms and amounts of mucins, which contribute to tumor development by regulating cell growth, survival, adhesion, invasion and immune responses. CD43, a type I transmembrane protein, is a mucin-like molecule expressed under normal physiological conditions by most hematopoietic cell types. CD43 is also frequently expressed in early stages of colorectal adenomas, but not in normal colon epithelial cells. The role of CD43 in colon tumor cells is unknown. The purpose of the present study was to investigate the expression and function of CD43 in tumor cells and evaluate the potential role of CD43 in colon tumor development.We have studied CD43 expression at both mRNA and protein levels by RT-PCR, flow cytometry, western blot and immunohistochemistry in tumor cell lines of different tissue origin. CD43 was found ubiquitously expressed in all studied cell lines, although with various expression levels and glycoforms. CD43 expression was shown in the colon adenocarcinoma cell lines COLO 205, Caco-2, SW 480, HT-29 and DLD-1.The proteolytic processing of type I transmembrane proteins by the ×-secretase complex is an important mechanism for their functional regulation. Previous results of our group suggested that the cytoplasmic tail of CD43 could localize to the cell nucleus and act as a signaling molecule. This could be linked to our observation that CD43 is a substrate for g-secretase that releases the intracellular part of CD43 into the cytosol.To study the function of CD43 in colon tumors, we increased the CD43 protein level by transient transfections or by using a tetracycline-regulated expression system. In the SW 480 cell line, CD43 overexpression inhibited nuclear localization of the transcription factor NF-kappaB p65 and suppressed expression of the chemokines MCP-1, IL-8 and GRO-alpha. It is known that activated tumor suppressors, such as p53 and ARF, inhibit the transcriptional activity of NF-kappaB. In fact, overexpression of CD43 activated p53 when ARF was present and resulted in cell death. However, CD43 overexpression promoted colony formation, cell growth and cell survival in the cells lacking either expression of ARF or p53. Moreover, high expression of CD43 helped cells to evade Fas-mediated apoptosis. This provides the first indication that expression of CD43 in a certain cellular context enhances a transformed phenotype of the cell.In summary, the results give new insights in the abnormal expression and function of CD43. This thesis suggests that CD43 expression by tumor cells may contribute to immune surveillance, cell growth, cell survival, and evasion of apoptosis.