Myoferlin regulates epithelial cancer cell plasticity and migration through autocrine TGF-β1 signaling
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Victoria R. Barnhouse1,*, Jessica L. Weist1,2,*, Vasudha C. Shukla1, Samir N. Ghadiali1,3,4, Douglas A. Kniss1,5 and Jennifer L. Leight1,2
1Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, 43210 Ohio, USA
2The James Comprehensive Cancer Center, The Ohio State University, Columbus, 43210 Ohio, USA
3Dorothy M. Davis Heart and Lung Research Institute, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, 43210 Ohio, USA
4Department of Internal Medicine (Division of Pulmonary, Critical Care and Sleep Medicine), College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, 43210 Ohio, USA
5Department of Obstetrics and Gynecology (Division of Maternal-Fetal Medicine and Laboratory of Perinatal Research), College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, 43210 Ohio, USA
*These authors contributed equally to this work
Jennifer L. Leight, email: email@example.com
Keywords: myoferlin; TGF-beta; cancer; epithelial-mesenchymal transition; mesenchymal-epithelial transition
Received: January 15, 2018 Accepted: March 15, 2018 Published: April 10, 2018
Epithelial cancer cells can undergo an epithelial-mesenchymal transition (EMT), a complex genetic program that enables cells to break free from the primary tumor, breach the basement membrane, invade through the stroma and metastasize to distant organs. Myoferlin (MYOF), a protein involved in plasma membrane function and repair, is overexpressed in several invasive cancer cell lines. Depletion of myoferlin in the human breast cancer cell line MDA-MB-231 (MDA-231MYOFKD) reduced migration and invasion and caused the cells to revert to an epithelial phenotype. To test if this mesenchymal-epithelial transition was durable, MDA-231MYOFKD cells were treated with TGF-β1, a potent stimulus of EMT. After 48 hr with TGF-β1, MDA-231MYOFKD cells underwent an EMT. TGF-β1 treatment also decreased directional cell motility toward more random migration, similar to the highly invasive control cells. To probe the potential mechanism of MYOF function, we examined TGF-β1 receptor signaling. MDA-MB-231 growth and survival has been previously shown to be regulated by autocrine TGF-β1. We hypothesized that MYOF depletion may result in the dysregulation of TGF-β1 signaling, thwarting EMT. To investigate this hypothesis, we examined production of endogenous TGF-β1 and observed a decrease in TGF-β1 protein secretion and mRNA transcription. To determine if TGF-β1 was required to maintain the mesenchymal phenotype, TGF-β receptor signaling was inhibited with a small molecule inhibitor, resulting in decreased expression of several mesenchymal markers. These results identify a novel pathway in the regulation of autocrine TGF-β signaling and a mechanism by which MYOF regulates cellular phenotype and invasive capacity of human breast cancer cells.
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