Abstract
Malignant transformation is characterized by a phenotype “switch” from E- to N-cadherin – a major hallmark of epithelial to mesenchymal transition (EMT). The increased expression of N-cadherin is commonly followed by a growing capacity for migration as well as resistance to apoptosis. Integrin Linked Kinase (ILK) is a key molecule involved in EMT and progression of cancer cells. ILK is known as a major signaling mediator involved in cadherin switch, but the specific mechanism through which ILK modulates N-cadherin expression is still not clear.Studies were carried out on human melanoma WM793 and 1205Lu cell lines. Expression of proteins was analyzed using PCR and Western Blot; siRNA transfection was done for ILK. Analysis of cell signaling pathways was monitored with phospho-specific antibodies. Subcellular localization of protein was studied using the ProteoExtract Subcellular Kit and Western blot analysis.Our data show that ILK knockdown by siRNA did suppress N-cadherin expression in melanoma, but only at the protein level. The ILK silencing-induced decrease of N-cadherin membranous expression in melanoma highlights the likely crucial role of ILK in the coordination of membrane trafficking through alteration of Rab expression. It is essential to understand the molecular mechanism of increased N-cadherin expression in cancer to possibly use it in the search of new therapeutic targets.
Highlights
A reduction or loss in the expression of E-cadherin and induction of N-cadherin expression has been recognized as an important primary event in melanoma progression [1]
We showed that silencing of Integrin Linked Kinase (ILK) in melanoma cells resulted in the decrease of an important Epithelial Mesenchymal Transition (EMT) marker – N-cadherin expression on the protein level
We previously showed that ILK can regulate the N-cadherin expression through an unknown mechanism only on the protein level in melanoma [5], and can instigate cadherin switch of bladder cancer through transcriptional regulation by Twsit-1, Zeb-1, Snail and poly-ADP-ribose polymerase 1 ⁎ Corresponding author (PARP-1) [19]
Summary
A reduction or loss in the expression of E-cadherin and induction of N-cadherin expression has been recognized as an important primary event in melanoma progression [1]. N-cadherin is involved in the process allowing for dissemination of melanoma cells from the original tissue to distant organs; the expression of N-cadherin is responsible for increased proliferation and invasion of melanoma cells [3,4]. We showed that silencing of ILK in melanoma cells resulted in the decrease of an important EMT marker – N-cadherin expression on the protein level. A wealth of evidence points to endocytosis and recycling as important factors in the regulation of membranous expression of N-cadherin [8,9,10]. The receptor clearance defines the specificity with which a cell can react to extracellular stimuli. This shows that endocytosis may govern many cellular signaling processes, as well as EMT. Ras-associated binding (Rab)-GTPases are members of the Ras family of small GTPases and they are responsible
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