Differential expression of the h-DLG oncosuppressor as a progression marker to malignancy in histological samples derived from HPV-associated lesions

CAVATORTA, ANA LAURA; FUMERO, GASTÓN; CHOUHY, DIEGO; AGUIRRE, ROXANA; NOCITO, ANA LIA; GIRI, ADRIANA A.; BANKS, LAWRENCE; GARDIOL, DANIELA

Trieste, Italia

Congreso; ICGEB DNA Tumour Virus Meeting; 2003

International Centre of Genetic Engineering and Biotechnology (ICGEB)

HPV E6 oncoproteins target h-Dlg for ubiquitin-mediated proteolysis. h-Dlg oncosuppressor is localized at cell-cell interaction sites and is involved in cell polarity, cell adhesion and regulation of cell proliferation. To evaluate the contribution of Dlg E6-mediated degradation in the progression to malignancy in HPV infections we investigated by immunohistochemistry Dlg cell expression and its localization in biopsies derived from HPV-associated lesions. We analyzed the stratified epithelium of ectocervical, laryngeal, vulvar and nasal samples, and the association of HPV with these lesions was ascertained by a PCR-colorimetric method developed in our laboratory. Ectocervical samples were morphological classified as squamous intraepithelial lesion (SIL) of low (LSIL) or high-grade (HSIL) or invasive carcinoma. In normal tissue Dlg was expressed in the cytoplasm of the basal cells and in regions of cell contacts at the parabasal and intermediate layers. Dlg was absent in the uppermost differentiated cellular strata. In the SIL samples, we observed differences regarding Dlg cell localization and distribution within the epithelium. In addition, the expression level was higher than in normal tissue. These differences increased with the severity of the lesions suggesting that alterations in Dlg expression and distribution contribute to the progression of SIL. Dlg levels were extremely weak or even absent in invasive carcinoma samples and its absence in invasive cells may be associated with the malignant phenotype. For biopsies derived from other anatomical sites, the patterns of Dlg inmunostaining were similar to those of cervical samples considering the same lesion grade. Experiments are in progress to establish if the absence of Dlg in invasive carcinoma is due to a deregulated expression of HPV E6 leading to a highly increased degradation of Dlg or if it is a general process common to other invasive cancers not related to HPV.