Kawaguchi, Makoto Niigata Rosai Hospital|Nagoya City University
Hara, Noboru Niigata University
Bilim, Vladimir Niigata University
Koike, Hiroshi Niigata Rosai Hospital
Suzuki, Mituko University of Ghana|Tokyo Medical and Dental University
Kim, Tae-Sun Nagoya City University
Gao, Nan Nagoya City University
Dong, Yu Nagoya City University
Zhang, Sheng Nagoya City University|Kanazawa Medical University
Fujinawa, Yuji Niigata Rosai Hospital
Yamamoto, Osamu Niigata Rosai Hospital
Ito, Hiromi Yamagata University
Tomita, Yoshihiko Niigata University
Naruse, Yuchi University of Toyama
Sakamaki, Akira Ooshima Kurumi Hospital
Ishii, Yoko University of Toyama
Tsuneyama, Koichi Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Inoue, Masaaki Shimonoseki City Hospital
Itoh, Johbu Tokai University
Yasuda, Masanori Saitama Medical University
Sakata, Nobuo Showa Pharmaceutical University
Jung, Cha-Gyun Nagoya City University
Kanazawa, Satoshi Nagoya City University
Akatsu, Hiroyasu Nagoya City University
Minato, Hiroshi Kanazawa Medical University
Nojima, Takayuki Kanazawa Medical University
Asai, Kiyofumi Nagoya City University
Miura, Yutaka Nagoya City University
urothelial bladder carcinoma
nuclear localization signals
Background: 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. Here, we examined the diagnostic value of the intracellular localization of ATBF1 as a marker for the identification of high risk urothelial bladder carcinoma.
Methods: Seven 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.
Results: ATBF1 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).
Conclusions: Cleavage 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.
BioMed Central|Springer Nature
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
|DOI (Published Version)|
|URL ( Publisher's Version )|
BMCCan_16_805.pdf 1.57 MB