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Urol Oncol. 2018 Apr;36(4):161.e1-161.e6. doi: 10.1016/j.urolonc.2017.12.007. Epub 2017 Dec 27.

Overexpression of semaphorin 3A in patients with urothelial cancer.

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The Department of Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel.
The Department of Mathematic, Technion, Israeli Institute of Technology, Haifa, Israel.
The Department of Pathology, Bnai Zion Medical Center, Haifa, Israel.
The Department of Urology, Bnai Zion Medical Center, Haifa, Israel. Electronic address:



A highly sensitive and specific urine marker for the detection of recurrent urothelial cancer and for screening healthy population or people at risk for urothelial cancer has not been found yet. As urine cytology is not sensitive enough, patients with non-muscle-invasive bladder cancer need lifelong follow-up involving multiple invasive cystoscopies. Our aims of study were to examine the expression of semaphorin 3A in urothelial cancer patients and to evaluate semaphorin 3A as a potential marker for urothelial cancer.


Urine samples were taken from patients with known bladder tumor, hospitalized for transurethral resection of lesions, from patients with history of urothelial cancer admitted for endoscopic follow up, from patients with other nonmalignant urological conditions such as prostatic hyperplasia, stress incontinence, urethral stricture, ureteral and kidney stones, and from healthy volunteers with no history of urothelial malignancy and no urological symptoms. Semaphorin 3A (sema3A) protein level was measured using enzyme-linked immunosorbent assay in every sample and levels were correlated with endoscopic and pathological findings. In addition, we performed immunohistochemically staining with semaphorin 3A of 15 tissue samples (various tumors and normal bladder tissues).


A total of 183 urine samples were tested. Out of them, 116 patients (mean age 70.7; 94 males and 22 females) had positive cystoscopy, and 67 (mean age 64.7; 51 males and 16 females) had negative cystoscopy. Higher sema3A values were significantly correlated (P = 0.006) with presence of urothelial cancer, as determined by positive cystoscopy or urethroscopy and pathological biopsy. Sema3A levels also showed positive correlation with the number of tumors. Sema3A levels combined with urine cytology showed much higher sensitivity compared with cytology alone (66% vs. 33%), with smaller reduction of specificity (77% vs. 90%). Immunohistochemical staining showed intense staining in high stage and grade tumors, and almost no staining in normal tissue.


Semaphorin 3A is overexpressed in urothelial cancer patients, as evidenced both in its presence in urine and in bladder tissue. Semaphorin 3A in urine is a promising potential urothelial cancer biomarker either independently or in conjunction with cytology. Further tests are needed to elucidate the sex difference in the expression of Sema3A in the urine of bladder cancer patients.


Noninvasive detection; Overexpression; Urine, Semaphoring 3a; Urothelial cancer

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