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The role of myoferlin and dysferlin in lung epithelial cell membrane functions and lung cancer Leung, Suk Kei

Abstract

Lung cancer is the deadliest cancer in the world. Almost all lung cancers originate from epithelial tissues within the lung. Lung epithelium provides a barrier to inhaled particulate matter and pathogens; hence, maintaining the normal epithelial integrity is important in defending against these foreign substances. Maintenance of lung epithelial integrity involves the collaboration of transmembrane and cytoplasmic proteins to form cellular junctions. Delivery of these junctional proteins to the cell membrane requires vesicle trafficking and membrane fusion events. Additionally, in the setting of lung tumors, vesicle trafficking and membrane fusion are also important in membrane remodeling and cell survival to facilitate tumor growth. Myoferlin and dysferlin are two transmembrane proteins that contribute to the repair of damaged cell membranes and expression of membrane proteins in multiple cell types. Based on the known functions of myoferlin and dysferlin in non-lung cells, I hypothesized that myoferlin and dysferlin have distinctive roles in normal and neoplastic lung epithelial cells. I provide evidence that attenuated myoferlin expression in human airway epithelial cells causes cell appearance changes, loss of adhesion and ultimately apoptosis. Loss of cell adhesion was associated with decreased expression of junctional protein zonula occludens 1 (ZO-1). Dysferlin gene silencing, on the other hand, did not have any effect on cell appearance, adhesion or ZO-1 expression. The pathophysiological role of myoferlin was further investigated in lung tumor. Myoferlin knockdown decreased both mouse lung tumor cell proliferation in vitro and solid lung tumor growth in a mouse tumor xenograft model. Subsequent investigation revealed that myoferlin knockdown impaired the resealing of ruptured membrane. These data have implications for the role of myoferlin in membrane remodeling that is essential for rapidly dividing tumor cells. In human lung tumor cells, myoferlin knockdown decreased both cell proliferation and invasion and these were attributed to decreased Akt activity. Since Akt activity is frequently hyperactivated during tumor development, these findings further support the possibility for new therapeutic strategies targeted at myoferlin for lung cancer. In summary, my work suggests that myoferlin has important functional roles in both normal and neoplastic lung epithelia.

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Attribution-NonCommercial-NoDerivs 2.5 Canada