Differential expression of the human homologue of Drosophila discs large oncosuppressor in histologic samples from human papillomavirus-associated lesions as a marker for progression to malignancy

High-risk HPVs play a causal role in the development of cervical cancer, and their E6 oncoproteins target h-DIg for ubiquitin-mediated proteolysis. The h-DIg oncosuppressor is associated with cell-cell interactions, and deregulation of these structures leads to defective cell adhesion, loss of cell polarity and unregulated proliferation. We evaluated the contribution of this E6 activity in the progression to malignancy in HPV infections by analyzing h-Dig expression in HPV-associated lesions. We analyzed h-Dig in cervical, laryngeal, vulvar, colon and kidney histologic samples by Dig immunohistochemistry. HPV association was ascertained by a PCR-colorimetric method. Although Dig was certainly expressed in intraepithelial cervical, vulvar and laryngeal HPV-associated lesions, its cellular and tissue distribution patterns were altered compared to normal tissue. However, marked reduction in Dig levels was observed in HPV-positive invasive cervical carcinomas. To elucidate whether the loss of Dig was significant for carcinogenesis in general, we investigated Dig expression in tumors not associated with HPV. In colon and kidney carcinomas, Dig was expressed, albeit with a. different pattern of distribution with respect to the normal tissue. The loss of Dig may be considered a late-stage marker in cervical carcinogenesis, but alterations in its expression and localization take place during the different dysplastic stages. Dig downregulation and/or alterations in its localization may contribute to transformation and may explain some of the characteristics of the malignant cells, such as loss of polarity and high migration ability. (C) 2004 Wiley-Liss, Inc.