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Int J Clin Exp Pathol 2013;6(11):2430-2440

Original Article
High expression of Notch ligand Jagged2 is associated with the metastasis and
recurrence in urothelial carcinoma of bladder

Wei Li, Min Liu, Yuan Feng, Yan-Fei Huang, Yun-Fei Xu, Jian-Ping Che, Guang-Chun Wang, Jun-Hua Zheng

Department of Urology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200072, China; Department of Nephrology, Nanjing
University Affiliated Drum Tower Hospital, Nanjing, Jiangsu, 210093, China; Department of Pathology, Immunology and Laboratory Medicine,
University of Florida, 32610, USA. Equal contributors.

Received August 3, 2013; Accepted August 18, 2013; Epub October 15, 2013; Published November 1, 2013

Abstract: Background: The Notch signaling pathway is closely related with human organ development and tumorgenisis. Jagged2 is among
the most popular topic in Notch studies currently. Recent studies found its vital role in tumor metastasis in breast cancer; however, its
expression profile and its prognostic value in urothelial carcinoma of bladder have not been investigated. Methods: Immunohistochemistry was
used to detect the expression of Jagged2 in 120 bladder urothelial carcinoma. Moreover, the expression of Jagged2 was analyzed by Western
blot in 60 bladder urothelial carcinoma and 20 normal epithelial tissues. MTT assay and flow cytometry and transwell assay were used to
examine the proliferative and invasive ability of bladder cancer cells with the treatment of GSIXX (the inhibitor of Jagged2). Prognostic value of
Jagged2 expression and its correlation with tumor metastasis and recurrence were evaluated, and the proliferative and invasive ability and cell
cycle process of the bladder cancer cells were detected as well. Results: There was a significantly higher Jagged2 expressions in bladder
urothelial carcinoma and highly invasive bladder T24 cells than those in bladder normal tissues and the superficial bladder BIU-87 cells.
Jagged2 expression was positively correlated with histological grade, p T stage, recurrence, and metastasis. With the increasing concentration
of GSIXX, we found that not only the cell proliferation and invasion activity decreased significantly, but also the cell cycle was blocked at G2/M
stage. Conclusions: Jagged2 expression status was closely correlated with important histopathologic characteristics (grades and stages) and
the recurrence and metastasis of bladder urothelial carcinomas. Furthermore, Jagged2 played an important function on the bladder cancer
cells’ proliferation by regulating the cancer cell cycle from G1/S to G2/M and probably promoted the invasion and metastasis of bladder cancer.

Keywords: Bladder urothelial carcinoma, Jagged2, histopathologic grade, clinical stage, GSIXX

Address correspondence to: Dr. Jun-Hua Zheng, Department of Urology, Shanghai Tenth People’s Hospital, Tongji University, No. 301,
Yanchang Mid-Road, Shanghai, 200072, China. E-mail: kidneyliu@163.com