The Role of Uroplakin IIIA (UPIIIA) Gene and its Protein in the Diagnosis of Bladder Cancer

Abstract

Urinary bladder cancer is a common disease worldwide. Bladder cancer ranks the ninth in worldwide with approximately 430,000 new cases diagnosed each year and more than 165,000 will succumb to the disease. Bladder cancer incidence rates are highest in Southern Europe and lowest in Western Africa. It was determined that bladder cancer affects men more frequently than women. Bladder cancer ranks the second after liver cancer among males in Egypt. It has been recorded that bladder cancer is the most common cancer in Egypt during the past 50 years. However, the frequency rate of bladder cancer has declined significantly during the last 25 years. This drop is mainly related to the control of Schistosomiasis. The main risk factor for bladder cancer in Egypt was urinary Schistosomiasis which was more frequent in Upper Egypt and its prevalence decreased when going north. Rising cigarette smoking is one of the most important risk factors that cause changes in bladder cancer risk in Egypt, which is now 32% among males but only 7% among females. The main symptom of bladder cancer is hematuria, but in some patients, there are no symptoms in an early stage. Early detection of cancers is essential for improved prognosis and long-term survival, and can only be beneficial regarding mortality if the high risk cancers are recognized and treated at a localized stage. Nowadays, bladder cancers can be diagnosed and followed-up using a combination of cystoscopic examination, cytology and histology. However, these methods are expensiveand highly subjective investigations and reveal little about the underlying molecular characteristics of the cancers (eg. bladder cancer in situ and upper tract disease).Accurate and sensitive detection of bladder cancer is critical to diagnose this deadly disease at an early stage, estimate prognosis, predict response to treatment, and monitor recurrence so high-quality detection methods are needed not only for initial diagnoses but also in surveillance for recurrent tumors. As the terminal differentiation products of human urothelium, uroplakins (UPs) would be expected to diminish during urothelialtumorigenesis. Surprisingly, recent studies found UPs to be retained even by well-advanced urothelial carcinomas, suggesting that the loss of UPs does not strictly parallel urothelial transformation. Uroplakins are the protein building blocks and differentiation-related membrane proteins of urothelium. Urothelial plaques exhibited typical 2D crystals of hexagonally packed 16-nm particles and contained four major proteins of 15,27, 28 and 47 kDa. These novel integral membrane proteins was named uroplakinsIa (27 kDa), Ib (28 kDa), II (15 kDa) and IIIa (47 kDa). The UPIIIA expresses in both normal bladder tissue and bladder carcinoma, but not in other normal and cancerous tissues. It could be a highly specific immunohistochemical markerfor urothelial tumors for the identification of primary andmetastatic urothelial carcinomas. Hence, the present study was conducted aiming to evaluate the role of uroplkin IIIA (UPIIIA) in the diagnosis and prognosis of bladder cancer. In order to achieve our aim, we investigated the expression level of UPIIIA gene and its protein in blood and urine of bladder cancer patients comparing with its corresponding values in healthy subjects and benign patients suffering from benign diseases in the urinary bladder system. Bladder cancer patients were observed for 3 years aiming to find prognostic value for UPIIIA. Atotal of 106subjects divided into: 1. Group 1:healthy subjects (25 individuals)(Control group). 2. Group 2: patients with benign urological disorders (20 individuals)[benign prostatic hyperplasia (BPH) (diagnosed with ultrasound and digital rectal examination [DRE]), urolithiasis(stones at kidney and urinary system)]( Benign group). 3. Group 3: cancer patients with no metastasis(Non metastatic bladder cancer patients) (52 patients). 4. Group 4: cancer patients with metastasis (9 patients) (metastatic bladder cancer patients). Cancer patients were observed for 3 years from the time of surgery. The UPIIIA mRNA level was detected in blood using Q-PCR, and in urine by Conventional PCR, while urinary UPIIIA protein was measured using ELISA .