A diagnostic marker for superficial urothelial bladder carcinoma: lack of nuclear ATBF1 (ZFHX3) by immunohistochemistry suggests malignant progression

BMC Cancer

Research Article

Nobuo Sakata¹  Masanori Yasuda²  Yuchi Naruse³  Akira Sakamaki⁴  Hiroyasu Akatsu⁵  Tae-Sun Kim⁶  Kiyofumi Asai⁶  Nan Gao⁶  Yutaka Miura⁶  Sheng Zhang⁷  Satoshi Kanazawa⁸  Cha-Gyun Jung⁹  Yu Dong^1,10  Koichi Tsuneyama^1,11  Takayuki Nojima^1,12  Hiroshi Minato^1,12  Yoko Ishii^1,13  Masaaki Inoue^1,14  Yuji Fujinawa^1,15  Osamu Yamamoto^1,15  Makoto Kawaguchi^1,16  Noboru Hara^1,17  Vladimir Bilim^1,17  Yoshihiko Tomita^1,17  Hiroshi Koike^1,18  Johbu Itoh^1,19  Hiromi Ito^2,20  Mituko Suzuki^2,21 

[1] Department of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, 194-8543, Machida, Tokyo, Japan;Department of Diagnostic Pathology, International Medical Center, Saitama Medical University, 1397-1 Yamane, 350-1298, Hidaka, Saitama, Japan;Department of Human Science and Fundamental Nursing, School of Nursing, University of Toyama, 2630 Sugitani, 930-0194, Toyama, Toyama, Japan;Department of Internal Medicine, Ooshima Kurumi Hospital, 48 Kitano, Ooshima, 939-0271, Imizu, Toyama, Japan;Department of Medicine for Aging in Place and Community-Based Medical Education, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, 467-8601, Mizuho-ku, Nagoya, Aichi, Japan;Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, 467-8601, Mizuho-ku, Nagoya, Aichi, Japan;Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, 467-8601, Mizuho-ku, Nagoya, Aichi, Japan;Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 11-1 Daigaku, Uchinada, 920-0293, Kahoku, Ishikawa, Japan;Department of Molecular and Cellular Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cyo, 467-8601, Mizuho-ku, Nagoya, Aichi, Japan;Department of Neurophysiology and Brain Science, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, 467-8601, Mizuho-ku, Nagoya, Aichi, Japan;Department of Oncology, Immunology and Surgery, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, 467-8601, Mizuho-ku, Nagoya, Aichi, Japan;Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Graduate School of Medicine, Tokushima University, 3-18-15 Kuramoto-cho, 770-8503, Tokushima, Tokushima, Japan;Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 11-1 Daigaku, Uchinada, 920-0293, Kahoku, Ishikawa, Japan;Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, 930-0194, Toyama, Toyama, Japan;Division of Chest Surgery, Shimonoseki City Hospital, Koyo-cho, 750-8520, Shimonoseki, Yamaguchi, Japan;Division of Diagnostic Pathology, Niigata Rosai Hospital, Japan Organization of Occupational Health and Safety, 1-7-12 Toh-un-cho, 942-8502, Johetsu, Niigata, Japan;Division of Diagnostic Pathology, Niigata Rosai Hospital, Japan Organization of Occupational Health and Safety, 1-7-12 Toh-un-cho, 942-8502, Johetsu, Niigata, Japan;Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, 467-8601, Mizuho-ku, Nagoya, Aichi, Japan;Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, 754 Ichiban-cho, Asahimachi-dohri, 951-8520, Cyuo-ku, Niigata, Niigata, Japan;Division of Urology, Niigata Rosai Hospital, Japan Organization of Occupational Health and Safety, 1-7-12 Toh-un-cho, 942-8502, Johetsu, Niigata, Japan;Education and Research Support Center, School of Medicine, Tokai University, 143 Shimokasuya, 259-1193, Isehara, Kanagawa, Japan;Laboratory of Molecular Oncology, Department of Urology, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, 990-9585, Yamagata, Yamagata, Japan;Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, LG 581, Accra, Ghana;Section of Environmental Parasitology, Faculty of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, 113-8510, Tokyo, Japan;

关键词: ATBF1;    urothelial bladder carcinoma;    nuclear localization signals;    prognostic marker;   

DOI  :  10.1186/s12885-016-2845-5

 received in 2015-09-07, accepted in 2016-10-06,  发布年份 2016

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2016