Research Article: Pathogenic and Diagnostic Potential of BLCA-1 and BLCA-4 Nuclear Proteins in Urothelial Cell Carcinoma of Human Bladder

Date Published: July 2, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Matteo Santoni, Francesco Catanzariti, Daniele Minardi, Luciano Burattini, Massimo Nabissi, Giovanni Muzzonigro, Stefano Cascinu, Giorgio Santoni.


Transitional cell carcinoma (TCC) of the bladder is one of the most common malignancies of genitourinary tract. Patients with bladder cancer need a life-long surveillance, directly due to the relatively high recurrence rate of this tumor. The use of cystoscopy represents the gold standard for the followup of previously treated patients. Nevertheless, several factors, including cost and invasiveness, render cystoscopy not ideal for routine controls. Advances in the identification of specific alterations in the nuclear structure of bladder cancer cells have opened novel diagnostic landscapes. The members of nuclear matrix protein family BLCA-1 and BLCA-4, are currently under evaluation as bladder cancer urinary markers. They are involved in tumour cell proliferation, survival, and angiogenesis. In this paper, we illustrate the role of BLCA-1 and BLCA-4 in bladder carcinogenesis and their potential exploitation as biomarkers in this cancer.

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Transitional cell carcinoma (TCC) represents more than 90% of bladder cancers [1], ranking among genitourinary malignancies only behind prostate cancer for frequency and estimated mortality. At initial diagnosis, more than 70% of bladder tumors are confined to the mucosa or lamina propria. Transurethral resection of nonmuscle invasive tumors can be accompanied by intrabladder therapy, depending on tumor depth and grade. However, more then 70% of patients can present tumor recurrences after treatment, with up to 30% of patients progressing to higher tumor stage and grade [2].

Changes in nuclear structure can affect gene expression, thus playing an important role in the carcinogenesis process [11]. In 1977, BerezneyandCoffey first described the nuclear matrix structure [12]. It is composed by protein components derived from three structural regions: a lamina with nuclear pores, the residual nucleoli, and an internal matrix framework connected to a residual nuclear layer containing pore complexes. Nuclear matrix represents an active environment where DNA replication [13, 14] and RNA synthesis take place [15, 16]. NMPs recognize and bind to specific DNA sequences called scaffold/matrix attachment regions (S/MAR), partitioning DNA into functional loop domains. S/MARs are involved in chromosomal replication, transcription, recombination, and condensation. They interact with topoisomerase II, identified by Berrios et al. in 1985 as a major polypeptide component of the Drosophila nuclear matrix-pore complex-lamina fraction [17]. The S/MAR interacting elements also include lamins A and C [18], Poly(ADP-ribose)polymerase 1 and 2 (PARP-1, PARP-2) [19], and CCCTC-binding factor (CTCF) [20] that binds to the regulatory regions of c-myc gene [21]. Moreover, certain S/MARs require adjacent transcription factors to become active [22]. Therefore, nuclear morphology is deeply influenced by NMPs. Based on these findings, NMPs have been investigated as potential cancer markers. Moreover, the discovery that NMPs are released into urine and serum has suggested their exploitation for cancer diagnosis.

Bladder cancer is the fourth most common cancer in men and the ninth most common in women. Despite recent advances, the molecular mechanisms underlying bladder carcinogenesis are still not fully elucidated so far. The screening of high-risk population has become critical to diminish the mortality. Current methods used for a proper diagnosis of bladder cancer mainly rely on cystoscopy, which can be associated with biopsy or resection. The importance of detecting bladder cancer at the early stage is clearly demonstrated by the 94% of 5-year survival rate registered in patients with localized disease. Cytology has represented for decades the noninvasive standard for the detection of urinary bladder cancer cells. However, cytology lacks sensitivity, particularly for low-grade tumors. In the last years, the list of identified urinary markers in course of evaluation has been rapidly enlarged. Preliminary data on emerging markers have shown higher sensitivity than routine urinary cytology, especially when a panel of markers were used. The urinary markers and tests under investigation include BTA, NMP22, BLCA-1, BLCA-4, hyaluronic acid, hyaluronidase, cytokeratin-8, cytokeratin-18, cytokeratin-19, telomerase, Immunocyt, Quanticyt, FDP, FISH, and CYFRA-21-1.