Objectives: Endometrial cancer is one of the most common gynecological malignancies affecting post-menopausal women, yet the underlying mechanisms are not well understood. Dystroglycan (DG) is a large glycoprotein, consisting of α- and β-subunits, which are derived from a single gene. While β-DG is anchored to the plasma membrane, α-DG is non-covalently associated to the extracellular N-terminus of β-DG. Post-translational removal of the N-terminus of α-DG (α-DG-N) by a furin-like enzyme has been linked to a variety of cancers. However, the functional significance of α-DG-N removal is unknown. Previous studies in our laboratory have demonstrated that furin is significantly up-regulated in endometrial cancer of post-menopausal women. However, it is unknown whether α-DG-N removal occurs in endometrial cancer. In this study we investigated α-DG expression and the importance of α-DG-N removal in post-menopausal endometrial cancer.
Methods and Results: We demonstrated by immunohistochemical analysis that α-DG-N removal occurred predominantly in early stage endometrial cancer tissues. We further found by ELISA that the cleaved α-DG-N was significantly elevated in the uterine lavage of early grade endometrial cancer patients. Functionally, α-DG-N removal significantly decreased the tight junction integrity and polarity of the endometrial epithelial cells, promoting the loss of polarity markers scribble and atypical protein kinase C (aPKC) and reducing the trans-epithelial electrical resistance. In addition, the removal of α-DG-N sensitized the cells for estrogen-dependent proliferation.
Conclusion: Our results suggest that α-DG-N removal plays an important role in early stage development of endometrial cancer, and that the elevated levels of α-DG-N in uterine fluid may provide a biomarker for early detection of endometrial cancer.