The significance of post-translational removal of α-DG-N in early stage endometrial cancer development
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Sophea Heng1,2,3, Jemma Evans1,2,4, Lois A. Salamonsen1,2,4, Tom W. Jobling4,5 and Guiying Nie1,2,3
1Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia
2Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
3Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
4Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
5Epworth Research Institute, Epworth Health Care, Richmond, Victoria, Australia
Guiying Nie, email: [email protected]
Keywords: endometrial cancer, dystroglycan, tight junction, cell polarity, estrogen
Received: October 25, 2016 Accepted: April 11, 2017 Published: April 20, 2017
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 that are non-covalently associated with each other. Modifications to α-DG have been linked to a variety of cancers, where the N-terminus of α-DG (α-DG-N) is post-translationally removed by a furin-like enzyme. However, the functional significance of α-DG-N removal is unknown. Our previous studies have established that the α-DG cleavage enzyme furin is significantly up-regulated in endometrial cancer. This study aimed to investigate the importance of α-DG-N removal in post-menopausal endometrial cancer. We demonstrated that α-DG-N removal predominantly occurred in early stage endometrial cancer tissues, and that the cleaved α-DG-N was significantly elevated in the uterine lavage of early grade endometrial cancer patients. Furthermore, 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. The removal of α-DG-N also sensitized the cells for estrogen-dependent proliferation. These results strongly 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.
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