title: A diagnostic marker for superficial urothelial bladder carcinoma: lack of nuclear ATBF1 (ZFHX3) by immunohistochemistry suggests malignant progression.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
authors.affiliation: Division of Diagnostic Pathology, Niigata Rosai Hospital, Japan Organization of Occupational Health and Safety, 1-7-12 Toh-un-cho, Johetsu, Niigata, 942-8502, Japan.|Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawaguchi
authors.affiliation: Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, 754 Ichiban-cho, Asahimachi-dohri, Cyuo-ku, Niigata, Niigata, 951-8520, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Hara
authors.affiliation: Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, 754 Ichiban-cho, Asahimachi-dohri, Cyuo-ku, Niigata, Niigata, 951-8520, Japan.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bilim
authors.affiliation: Division of Urology, Niigata Rosai Hospital, Japan Organization of Occupational Health and Safety, 1-7-12 Toh-un-cho, Johetsu, Niigata, 942-8502, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koike
authors.affiliation: Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Accra, LG 581, Ghana.|Section of Environmental Parasitology, Faculty of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: Mituko
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
authors.forename: Tae-Sun
authors.initials: TS
authors.lastname: Kim
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
authors.affiliation: Department of Oncology, Immunology and Surgery, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.|Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 11-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Division of Diagnostic Pathology, Niigata Rosai Hospital, Japan Organization of Occupational Health and Safety, 1-7-12 Toh-un-cho, Johetsu, Niigata, 942-8502, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Fujinawa
authors.affiliation: Division of Diagnostic Pathology, Niigata Rosai Hospital, Japan Organization of Occupational Health and Safety, 1-7-12 Toh-un-cho, Johetsu, Niigata, 942-8502, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Molecular Oncology, Department of Urology, School of Medicine, Yamagata University, 2-2-2 Iida-nishi, Yamagata, Yamagata, 990-9585, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Division of Urology, Department of Regenerative and Transplant Medicine, Graduate School of Medical and Dental Sciences, Niigata University, 754 Ichiban-cho, Asahimachi-dohri, Cyuo-ku, Niigata, Niigata, 951-8520, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Department of Human Science and Fundamental Nursing, School of Nursing, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
authors.forename: Yuchi
authors.initials: Y
authors.lastname: Naruse
authors.affiliation: Department of Internal Medicine, Ooshima Kurumi Hospital, 48 Kitano, Ooshima, Imizu, Toyama, 939-0271, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Sakamaki
authors.affiliation: Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, Toyama, 930-0194, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute of Biomedical Sciences, Graduate School of Medicine, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Division of Chest Surgery, Shimonoseki City Hospital, Koyo-cho, Shimonoseki, Yamaguchi, 750-8520, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Education and Research Support Center, School of Medicine, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
authors.forename: Johbu
authors.initials: J
authors.lastname: Itoh
authors.affiliation: Department of Diagnostic Pathology, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yasuda
authors.affiliation: Department of Biochemistry, Showa Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida, Tokyo, 194-8543, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakata
authors.affiliation: Department of Neurophysiology and Brain Science, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
authors.forename: Cha-Gyun
authors.initials: CG
authors.lastname: Jung
authors.affiliation: Department of Molecular and Cellular Biology, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cyo, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kanazawa
authors.affiliation: Department of Medicine for Aging in Place and Community-Based Medical Education, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.affiliation: Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 11-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Minato
authors.affiliation: Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 11-1 Daigaku, Uchinada, Kahoku, Ishikawa, 920-0293, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nojima
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Asai
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Sciences, Nagoya City University, 1-Chome, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan. miura-ngi@umin.net.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Miura
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D019556:COS Cells; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; C071660:ZFHX3 protein, human
keywords: ATBF1; nuclear localization signals; prognostic marker; urothelial bladder carcinoma