Down-regulation of DOC-2 in colorectal cancer points to its role as a tumor suppressor in this malignancy

PURPOSE: Colorectal cancer is the second most common cause of cancer death and the fourth most prevalent carcinoma in the Western world. Loss of tumor-suppressor gene function in colon cancer leads to ineffective negative growth regulation that is normally exerted by growth-suppressing factors. DOC-2/hDAB2 is a newly identified candidate tumor-suppressor gene in ovarian cancer and choriocarcinoma. In these tumors it negatively influences mitogenic signal transduction of growth factors and blocks ras activity. In the present study we sought to determine the role of DOC-2 in colorectal cancer. METHODS: DOC-2 expression was analyzed by Northern blot analysis, in situ hybridization, and immunohistochemistry in 27 primary and metastatic colorectal cancers and in 15 normal colon tissues in correlation with clinicopathologic data. RESULTS: Northern blot analysis demonstrated a decrease of DOC-2 messenger RNA levels in primary and metastatic colorectal cancers compared with normal controls. In normal colorectal tissues, DOC-2 immunoreactivity was strongly present on the surface columnar epithelial cells. In contrast, DOC-2 immunoreactivity was weak to moderate in the epithelium of colorectal cancers, and the intensity of the signals in colorectal cancer was greatly decreased compared with the normal colorectal tissues. In addition, DOC-2 immunoreactivity in lymph node and liver metastasis was weak to absent in the cancer cells and significantly decreased compared with their primary tumors. CONCLUSIONS: The expression of DOC-2 is down-regulated in primary tumors and metastases of colorectal cancer, which suggests that DOC-2 functions as a tumor suppressor in this malignancy.