Maspin expression in CIN 3, microinvasive squamous cell carcinoma, and invasive squamous cell carcinoma of the uterine cervix.

Maspin is a serine protease inhibitor with tumor suppression activity. It is expressed in normal breast and prostate tissue but is downregulated or absent in breast and prostate tumors. Recent reports have shown that decreased expression is associated with a greater propensity for metastasis in oral squamous cell carcinomas. We know that some high-grade cervical intraepithelial neoplasia progress to invasive carcinomas while others either persist at the same degree of atypia or regress. The pattern of maspin expression in cervical intraepithelial neoplasia-grade 3, microinvasive squamous carcinomas and overtly invasive squamous cell carcinomas of the uterine cervix was studied to determine the relationship between the extent of maspin expression and the progression of cervical intraepithelial neoplasia to squamous cell carcinoma. In total, 36 cases were evaluated: 18 cases of cervical intraepithelial neoplasia-grade 3, seven cases of microinvasive squamous cell carcinoma and 11 cases of invasive squamous cell carcinoma. A monoclonal antibody was used on paraffin-embedded tissues. Immunoreactivity was scored semiquantitatively using a scale of 0-3. The sums of the scores of the different groups were compared using the Mann-Whitney U-test. A significant decrease in maspin scores was noted between cervical intraepithelial neoplasia-grade 3 vs invasive squamous cell carcinoma (P<0.005), microinvasive squamous cell carcinoma vs invasive squamous cell carcinoma (P<0.05), and cervical intraepithelial neoplasia-grade 3 vs tumor emboli (P<0.005). Although not statistically significant, scores of cervical intraepithelial neoplasia-grade 3 associated with invasive squamous cell carcinoma were lower compared to that cervical intraepithelial neoplasia-grade 3 without invasive squamous cell carcinoma. These findings suggest that maspin likely plays a role in disease progression from in situ to invasive carcinoma. Virtual absence of maspin immunopositivity in tumor emboli indicates that maspin may also play a role in metastasis.

The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1.

The von Hippel-Lindau disease gene (VHL) is the causative gene for most adult renal cancers. However, the mechanism by which VHL protein functions as a renal tumor suppressor remains largely unknown. To identify low occupancy VHL protein partners with potential relevance to renal cancer, we screened a human kidney library against human VHL p30 using a yeast two-hybrid approach. Jade-1 (gene for Apoptosis and Differentiation in Epithelia) encodes a previously uncharacterized 64-kDa protein that interacts strongly with VHL protein and is most highly expressed in kidney. Jade-1 protein is short-lived and contains a candidate destabilizing (PEST) motif and plant homeodomains that are not required for the VHL interaction. Jade-1 is abundant in proximal tubule cells, which are clear-cell renal cancer precursors, and expression increases with differentiation. Jade-1 is expressed in cytoplasm and the nucleus diffusely and in speckles, where it partly colocalizes with VHL. VHL reintroduction into renal cancer cells increases endogenous Jade-1 protein abundance up to 10-fold. Furthermore, VHL increases Jade-1 protein half-life up to 3-fold. Thus, direct protein stabilization is identified as a new VHL function. Moreover, Jade-1 protein represents a novel candidate regulatory factor in VHL-mediated renal tumor suppression.