Clusterin Expression in Endometrial Cancer

Whereas the aetiopathogenesis of endometrial cancer development and progression is still obscure, recent studies have demonstrated that the expression of genes related to cell adhesion, growth, cell cycle and apoptosis is altered or lost during progression from normal to invasive endometrial cancer. Endometrial tissue is a very highly interactive system involving different cell types which relies on a complex network of intercellular and intracellular signaling in which cell cycle proteins, estrogens, pro-inflammatory species and growth factors strictly cross talk. In this regard, it may be relevant the study of regulation of gene expression and cell cycle alterations in both human cell lines and neoplastic tissue specimens experimental models. In the recent years we have focused our attention on the role of growth factors and adhesion factors in the aetiopathogenesis of human proliferating diseases (thyroid, mammary, prostate and endometrial umors). Our studies yielded the first evidence of a transcriptional and a post-transcriptional regulation of the expression of these factors during cellular transformations leading to malignant transformation. We are actually interested to clarify the relations between the cell cycle and apoptosis regulatory proteins, estrogens, proinflammatory species and growth factors. The aim of our study is to investigate how clusterin expression and functions are modulated under strogen stimulation in normal uterine tissue and in malignant tissue. Clusterin, is the first gene described having diametrically opposite hormonal control in a normal tissue and in tumours derived from that tissue. Clusterin is a ubiquitously expressed secreted protein whose presumed functions are still controversial. The prevailing hypothesis on its biological role, however, suggests that it is involved in the clearance of toxic substances from extracellular spaces through its ability to bind to unfolded proteins, cell debris, or immune complexes. Other studies have enlightened an antiapoptotic activity, protecting cultured cell lines against a variety of stress signals. An opposite function has been assigned to the nuclear form of clusterin, which appear to marks cells for apoptosis. Furthermore, the expression of Clusterin mRNA in vitro appears to accurately reflect the expression of the gene in primary and metastatic tumours derived from cells in vivo. In this light we examined Clusterin expression at mRNA levels in 11 endometrial adenocarcinoma and in 9 endometrial hyperplastic tissues using Northern blotting analysis. The pattern of Clusterin expression was compared to that of endometrium of 14 normal cycling women. Our in vivo results demonstrated that, in secretive and atrophic endometrium, mRNA levels of Clusterin are respectively down-regulated and up-regulated compared to proliferative endometrium. The study of Clusterin expression in pathological tissues have shown that mRNA levels are up-regulated in both neoplastic and hyperplastic endometrium. This up-regulation in carcinoma cells confirm the function of secretive form of Clusterin as anti-apoptotic and cytoprotective form. So the overexpression of this protein in human neoplastic cells represent a protection from any apoptotic stimuli. As such, clusterin may represent a valuable marker gene in the search for transcription factors that contribute to the malignant transformation of the endometrium and possibly of other hormone-dependent tumours, such as the prostate and breast. A better understanding of these biological mechanisms will provide new molecular targets for innovative strategies of prevention and therapy of endometrial cancer and could be critical to devise novel diagnostic approaches.