Abstract
The process by which epithelial features are lost in favor of a mesenchymal phenotype is referred to as epithelial–mesenchymal transition (EMT). Most carcinomas use this mechanism to evade into neighboring tissues. Reduction or a loss of E-cadherin expression is a well-established hallmark of EMT. As a potent suppressor of E-cadherin, transcription factor ZEB1 is one of the key inducers of EMT, whose expression promotes tumorigenesis and metastasis of carcinomas. Bcl-2-associated athanogene 3 (BAG3) affects multifaceted cellular functions, including proliferation, apoptosis, cell adhesion and invasion, viral infection, and autophagy. Recently, we have reported a novel role of BAG3 implicated in EMT, while the mechanisms are poorly elucidated. The current study demonstrated that knockdown of BAG3 induced EMT, and increased cell migratory and invasiveness in thyroid cancer cells via transcriptional activation of ZEB1. We also found that BAG3 knockdown led to nuclear accumulation of β-catenin, which was responsible for the transcriptional activation of ZEB1. These results indicate BAG3 as a regulator of ZEB1 expression in EMT and as a regulator of metastasis in thyroid cancer cells, providing potential targets to prevent and/or treat thyroid cancer cell invasion and metastasis.
Highlights
Carcinoma tumors use unique mechanisms to evade from the primary tissue into surrounding tissues
We found that knockdown of Bcl-2-associated athanogene 3 (BAG3) significantly decreased expression of epithelial marker E-cadherin, but increased the expression of mesenchymal marker vimentin
In contrast to the current study, Iwasaki et al.[25] reported that BAG3 was localized to the leading edge of migrating cells, and BAG3 short hairpin RNA (shRNA) retrovirus-mediated the downregulation of BAG3, which in turn decreased the migration of COS7, ALVA31, Du145, and MCF7 cells using transwell chambers precoated with fibronectin
Summary
Carcinoma tumors use unique mechanisms to evade from the primary tissue into surrounding tissues. Molecular reprogramming as part of the epithelial–mesenchymal transition (EMT) is considered to be a crucial step involved in this process in most carcinomas.[2] EMT may facilitate epithelial cells to escape from the rigid structural constraints provided by the tissue architecture, during which an orchestrated series of transcriptional and morphological program take place, resulting in the loss of epithelial differentiation and acquisition of mesenchymal-like cellular competence of tumor cells.[3,4,5] During EMT procedure, the actin cytoskeleton is reorganized and cells acquire increased cell–matrix contacts, leading to dissociation from surrounding cells and enhanced migratory and invasive capabilities.[6] Reduction or a loss of E-cadherin expression has a crucial role in tumor progression to invasive cancer and is one of the well-established hallmarks of EMT.[7] In line with a role for EMT in cancer progression, E-cadherin is often lost in cancer tissues and its reduction is associated with a poor clinical prognosis of many cancers.[8].
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