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Colorectal cancer is the second leading cause of cancer related deaths in North America. CD44, a ubiquitously expressed transmembrane adhesion protein, is involved in fundamental aspects of cancer cell biology such as tumor stem cell phenotype, cell adhesion and invasion, and resistance to apoptosis. It is over-expressed in most human malignant tumors including human colon. Another protein with a major implication in colorectal carcinogenesis is p53, a tumor suppressor protein. It is widely known to play an important role in the control of cell cycle and apoptosis and is often referred to as a “guardian of the genome”. Mutations in the p53 gene result in decreased genetic stability, reduced apoptosis, and increased survival and propagation of cells with damaged DNA. The nuclear accumulation of the p53 protein has been reported in a variety of malignant tumors, including colon cancer. The number of mutations in p53 was found to increase as colorectal adenomas progress to carcinomas to metastatic carcinoma. To further delineate the role of p53 and CD44 in colon cancer, immunohistochemistry studies were carried out using tumors generated by HT-29 human colon cancer cells in nude mice after siRNA CD44 gene therapy, as compared to untreated control xenografts. Using this xenograft mouse model, which had a reduced CD44 expression after siRNA CD44 gene therapy, we were able to demonstrate a significant decrease in p53 expression that is associated with the inhibition of CD44 expression in tumors derived from human colon cancer cells. This study suggests that the association between decreased CD44 expression and decreased p53 expression could be a possible manifestation of a return to a less aggressive tumor phenotype after siRNA CD44 gene therapy, providing insights into the likely roles of CD44 and p53 in the regulation of apoptosis and cancer progression.