Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder.

Yoshitaka Itami,Shunta Hori,Youping Deng,Satoshi Anai,Hideki Furuya,Tomomi Fujii,Kiyohide Fujimoto,Takeshi Inoue,Yoshihiro Tatsumi,Vedbar S Khadka,Keiji Shimada,Yousuke Morizawa,Nobumichi Tanaka,Kota Iida,Yasushi Nakai,Sayuri Ohnishi,Makito Miyake,Daisuke Gotoh,Kenta Ohnishi

doi:10.3390/diagnostics10010054

Abstract

Disabled homolog-2 (DAB2) has been reported to be a tumor suppressor gene. However, a number of contrary studies suggested that DAB2 promotes tumor invasion in urothelial carcinoma of the bladder (UCB). Here, we investigated the clinical role and biological function of DAB2 in human UCB. Immunohistochemical staining analysis for DAB2 was carried out on UCB tissue specimens. DAB2 expression levels were compared with clinicopathological factors. DAB2 was knocked-down by small interfering RNA (siRNA) transfection, and then its effects on cell proliferation, invasion, and migration, and changes to epithelial-mesenchymal transition (EMT)-related proteins were evaluated. In our in vivo assays, tumor-bearing athymic nude mice subcutaneously inoculated with human UCB cells (MGH-U-3 or UM-UC-3) were treated by DAB2-targeting siRNA. Higher expression of DAB2 was associated with higher clinical T category, high tumor grade, and poor oncological outcome. The knock-down of DAB2 decreased both invasion and migration ability and expression of EMT-related proteins. Significant inhibitory effects on tumor growth and invasion were observed in xenograft tumors of UM-UC-3 treated by DAB2-targeting siRNA. Our findings suggested that DAB2 expression was associated with poor prognosis through increased oncogenic properties including tumor proliferation, migration, invasion, and enhancement of EMT in human UCB.

Highlights

Urothelial cancer of the bladder (UCB) is the second most frequent neoplasm of the urogenital organs [1] and is recognized to be a heterogeneous disease
The predominant locations of Disabled homolog-2 (DAB2) expression were in the cytoplasm of cancer and stromal cells
Nine genes were altered more than 2-fold in MGH-U-3 with HBdSF transfected with DAB2- targeting small interfering RNA (siRNA) as compared to MGH-U-3 cultured with HBdSF transfected with negative control siRNA (Figure 5C). These results suggested that certain interactive humoral proteins were released from HBdSF cells with DAB2 expression and that these factors may contribute to epithelial-mesenchymal transition (EMT) promotion in MGH-U-3 cells

Summary

Introduction

Urothelial cancer of the bladder (UCB) is the second most frequent neoplasm of the urogenital organs [1] and is recognized to be a heterogeneous disease. Cancer-specific survival of patients with category Ta UCB is favorable, but T1 non-muscle invasive bladder cancer (NMIBC) has the potential to progress to muscle-invasive bladder cancer (MIBC) [2]. The processes related to tumor growth, invasion, metastasis, and treatment resistance need to be explained. Tumor tissue consists of cancer cells and several types of stromal cells including macrophages, fibroblasts, and endothelial cells. Their interaction and crosstalk may influence the development of a cancer-related microenvironment for tumor growth and invasion

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Conclusion