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Expression of Transgenes in Native Bladder Urothelium Using Adenovirus-Mediated Transduction
Published on: October 6, 2022
Decreased DOC-2/DAB2 expression in urothelial carcinoma of the bladder
Jose A Karam1, Shahrokh F Shariat, Hong-Ying Huang
1Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Purpose:
DOC-2/DAB2 (differentially expressed in ovarian carcinoma-2/disabled-2), a potential tumor suppressor gene, is underexpressed in several cancers. Little is known about the expression of this gene in urothelial carcinoma of the bladder (UCB). We profiled DOC-2/DAB2 expression in mouse and human normal and neoplastic urothelia.
Experimental Design:
Immunohistochemical staining for DOC-2/DAB2 was carried out on tissue specimens from two transgenic mouse models with urothelium-specific molecular alterations and on a tissue microarray containing cores from 9 normal controls, 44 patients who underwent transurethral resection of the bladder tumor (TURBT), 195 patients who underwent radical cystectomy for UCB, and 39 lymph nodes with metastatic UCB.
Results:
Normal mouse urothelium stained uniformly with DOC-2/DAB2. Weaker staining was observed in low-grade, superficial papillary bladder tumors from transgenic mice harboring constitutively active Ha-Ras, whereas carcinoma in situ-like lesions and high-grade bladder tumors from transgenic mice expressing a SV40 T antigen completely lacked DOC-2/DAB2 expression. In human tissues, DOC-2/DAB2 expression was decreased in 11% of normal bladder specimens, 59% of TURBT specimens, 65% of radical cystectomy specimens, and 77% of the metastatic lymph node specimens. Decreased DOC-2/DAB2 expression was associated with advanced pathologic stage (P = 0.023), lymph node metastases (P = 0.050), and lymphovascular invasion (P < 0.001). In univariable, but not in multivariable analysis, decreased DOC-2/DAB2 was associated with an increased probability of bladder cancer recurrence (log-rank test, P = 0.020) and bladder cancer-specific mortality (log-rank test, P = 0.023).
Conclusions:
Decreased DOC-2/DAB2 expression seems to occur early in bladder tumorigenesis and becomes more prominent in advanced stages of UCB.
Insights
DOC-2/DAB2 (differentially expressed in ovarian carcinoma-2/disabled-2) expression decreases in bladder tumors, correlating with advanced stages and poorer outcomes. This suggests DOC-2/DAB2 may be an early marker for urothelial carcinoma of the bladder (UCB).
Area of Science:
- Oncology
- Molecular Biology
- Urology
Background:
- DOC-2/DAB2 (differentially expressed in ovarian carcinoma-2/disabled-2) is a potential tumor suppressor gene with known underexpression in various cancers.
- Limited information exists regarding DOC-2/DAB2 expression in urothelial carcinoma of the bladder (UCB).
Purpose of the Study:
- To investigate the expression profile of DOC-2/DAB2 in both normal and neoplastic mouse and human urothelia.
- To determine the association between DOC-2/DAB2 expression levels and the progression and clinical outcomes of UCB.
Main Methods:
- Immunohistochemical staining was performed on tissue specimens from transgenic mouse models and human UCB samples, including normal bladders, tumors (TURBT and radical cystectomy), and metastatic lymph nodes.
- Expression levels were analyzed in relation to tumor grade, stage, lymph node metastasis, lymphovascular invasion, recurrence, and mortality.
Main Results:
- Normal mouse urothelium exhibited uniform DOC-2/DAB2 staining.
- Decreased DOC-2/DAB2 expression was observed in human UCB tissues, with higher rates of decrease in advanced stages and metastatic lymph nodes (77%).
- Reduced DOC-2/DAB2 levels correlated with advanced pathologic stage, lymph node metastases, and lymphovascular invasion, and were linked to increased recurrence and mortality in univariable analysis.
Conclusions:
- Decreased DOC-2/DAB2 expression appears to be an early event in bladder cancer development.
- The progressive loss of DOC-2/DAB2 is associated with tumor progression and adverse clinical outcomes in UCB.
- DOC-2/DAB2 warrants further investigation as a potential biomarker for UCB.
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