Disabled Homolog 2 (DAB2) Protein in Tumor Microenvironment Correlates with Aggressive Phenotype in Human Urothelial Carcinoma of the Bladder
Yoshitaka Itami,
Makito Miyake,
Sayuri Ohnishi,
Yoshihiro Tatsumi,
Daisuke Gotoh,
Shunta Hori,
Yousuke Morizawa,
Kota Iida,
Kenta Ohnishi,
Yasushi Nakai,
Takeshi Inoue,
Satoshi Anai,
Nobumichi Tanaka,
Tomomi Fujii,
Keiji Shimada,
Hideki Furuya,
Vedbar S. Khadka,
Youping Deng,
Kiyohide Fujimoto
Affiliations
Yoshitaka Itami
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Makito Miyake
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Sayuri Ohnishi
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Yoshihiro Tatsumi
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Daisuke Gotoh
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Shunta Hori
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Yousuke Morizawa
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Kota Iida
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Kenta Ohnishi
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Yasushi Nakai
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Takeshi Inoue
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Satoshi Anai
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Nobumichi Tanaka
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Tomomi Fujii
Department of Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
Keiji Shimada
Department of Pathology, Nara City Hospital, 1-50-1 Higashi kidera-cho, Nara 630-8305, Japan
Hideki Furuya
Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Vedbar S. Khadka
Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA
Youping Deng
Bioinformatics Core, Department of Complementary and Integrative Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI 96813, USA
Kiyohide Fujimoto
Department of Urology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
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.
