SATB1 overexpression regulates the development and progression in bladder cancer through EMT.

Feng Wan,Shian Xing,Xingyuan Xiao,Youpeng Zhang,Zongwei Wang,Xuepan Chen,Zhineng Zhu,Hanqing Zeng,Zhaohui Zhu,Sen Li,Cameron Johnson,Wei Xiang,Jin Wang,Chao Cheng,Neil A Hotchin

doi:10.1371/journal.pone.0117518

Abstract

The global gene regulator Special AT-rich sequence-binding protein-1 (SATB1) has been reported to induce EMT-like changes and be associated with poor clinical outcome in several cancers. This study aims to evaluate whether SATB1 affects the biological behaviors of bladder transitional cell carcinoma (BTCC) and further elucidate if this effect works through an epithelial-mesenchymal transition (EMT) pathway. The expression of SATB1, E-cadherin (epithelial markers), vimentin (mesenchymal markers) in BTCC tissues and adjacent noncancerous tissues, as well as in two cell lines of bladder cancer were investigated. Whether the SATB1 expression is associated with clinicopathological factors or not was statistically analyzed. Cell invasion and migration, cell cycle, cell proliferation and apoptosis were evaluated in SATB1 knockdown and overexpressed cell lines. Our results showed that the expression of SATB1 was remarkably up-regulated both in BTCC tissues and in bladder cancer cell lines with high potential of metastasis. The results were also associated with EMT markers and poor prognosis of BTCC patients. Moreover, SATB1 induced EMT processes through downregulation of E-cadherin, upregulation of E-cadherin repressors (Snail, Slug and vimentin). SATB1 also promoted cell cycle progression, cell proliferation, cell invasion and cell migration, but did not alter cell survival. In conclusion, our results suggest that SATB1 plays a crucial role in the progression of bladder cancer by regulating genes controlling EMT processes. Further, it may be a novel therapeutic target for aggressive bladder cancers.

Highlights

Bladder cancer (BC) is one of the most common malignant neoplasms affecting the lining of the urinary bladder, with an estimated 386,300 new cases and 150,200 deaths from the disease worldwide, per year [1]
To investigate whether the abnormal expression of Special AT-rich binding protein 1 (SATB1) is related to bladder cancer development and progression and involved in regulating epithelial-mesenchymal transition (EMT) in human bladder cancer, immunohistochemistry, real-time RT-PCR and western blotting analyses were initially performed to identify the expression of SATB1
We found that there were remarkable changes in the expression levels of SATB1 and vimentin between non-muscle-invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) tissues, which revealed that MIBC tissues showed higher levels of SATB1 and vimentin than that in NMIBC tissues (Fig. 1A and C; ÃP < 0.05)

Summary

Introduction

Bladder cancer (BC) is one of the most common malignant neoplasms affecting the lining of the urinary bladder, with an estimated 386,300 new cases and 150,200 deaths from the disease worldwide, per year [1]. It has been generally acknowledged that poor prognosis of malignancies is associated with tumor aggressiveness. This occurs when noninvasive cells become invasive through several metastatic steps, such as the epithelial cells losing polarity and further invading vascular and lymphatic compartments [8]. The epithelial mesenchymal transition (EMT) is the key process which initially occurs during critical phases of embryonic development in which cells lose their epithelial characteristics and cell-cell contacts, and concomitantly acquire migratory and invasive properties of mesenchymal cells [9,10,11]. A growing body of evidence suggests that the EMT plays a pivotal role in the initiation and development of metastasis during tumor invasion and progression of bladder cancer in vivo and in vitro [16,17,18]

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