Poster Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Post-translational removal of α-DG-N is important for early stage endometrial cancer development (#317)

Sophea Heng 1 2 , Jemma Evans 1 2 , Lois Salamonsen 1 2 , Tom Jobling 3 4 , Guiying Nie 1 2
  1. Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
  3. Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia
  4. Epworth Research Institute, Epworth Health Care, Richmond, Victoria, Australia

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.