Abstract
BackgroundPathological stage and grade have limited ability to predict the outcomes of superficial urothelial bladder carcinoma at initial transurethral resection (TUR). AT-motif binding factor 1 (ATBF1) is a tumor suppressive transcription factor that is normally localized to the nucleus but has been detected in the cytoplasm in several cancers. Here, we examined the diagnostic value of the intracellular localization of ATBF1 as a marker for the identification of high risk urothelial bladder carcinoma.MethodsSeven anti-ATBF1 antibodies were generated to cover the entire ATBF1 sequence. Four human influenza hemagglutinin-derived amino acid sequence-tagged expression vectors with truncated ATBF1 cDNA were constructed to map the functional domains of nuclear localization signals (NLSs) with the consensus sequence KR[X10-12]K. A total of 117 samples from initial TUR of human bladder carcinomas were analyzed. None of the patients had received chemotherapy or radiotherapy before pathological evaluation.ResultsATBF1 nuclear localization was regulated synergistically by three NLSs on ATBF1. The cytoplasmic fragments of ATBF1 lacked NLSs. Patients were divided into two groups according to positive nuclear staining of ATBF1, and significant differences in overall survival (P = 0.021) and intravesical recurrence-free survival (P = 0.013) were detected between ATBF1+ (n = 110) and ATBF1− (n = 7) cases. Multivariate analysis revealed that ATBF1 staining was an independent prognostic factor for intravesical recurrence-free survival after adjusting for cellular grading and pathological staging (P = 0.008).ConclusionsCleavage of ATBF1 leads to the cytoplasmic localization of ATBF1 fragments and downregulates nuclear ATBF1. Alterations in the subcellular localization of ATBF1 due to fragmentation of the protein are related to the malignant character of urothelial carcinoma. Pathological evaluation using anti-ATBF1 antibodies enabled the identification of highly malignant cases that had been overlooked at initial TUR. Nuclear localization of ATBF1 indicates better prognosis of urothelial carcinoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2845-5) contains supplementary material, which is available to authorized users.
Highlights
Pathological stage and grade have limited ability to predict the outcomes of superficial urothelial bladder carcinoma at initial transurethral resection (TUR)
Alterations in the subcellular localization of AT-motif binding factor 1 (ATBF1) due to fragmentation of the protein are related to the malignant character of urothelial carcinoma
Mislocalization of ATBF1 in human urothelial carcinoma (UC) cells The transcription factor ATBF1 is a DNA-binding protein that is primarily localized in the nucleus and is involved in brain development; it regulates the expression of genes involved in cell cycle arrest and cell differentiation [14, 15]
Summary
Pathological stage and grade have limited ability to predict the outcomes of superficial urothelial bladder carcinoma at initial transurethral resection (TUR). AT-motif binding factor 1 (ATBF1) is a tumor suppressive transcription factor that is normally localized to the nucleus but has been detected in the cytoplasm in several cancers. Approximately 60 % of patients with superficial UC experience recurrence and 10–20 % progress to invasive cancer [1]. Standard prognostic features, such as pathological stage and grade, have limited ability to predict disease outcomes [2], underscoring the need to identify accurate markers to predict the prognosis of UC. The prognostic value of ATBF1 in patients with UC has not been investigated to date
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