title: Neonatal streptozotocin treatment causes type 1 diabetes and subsequent hepatocellular carcinoma in DIAR mice fed a normal diet.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) represents a major health challenge because of its increasing morbidity and mortality. The establishment of useful models of HCC can significantly contribute to unveiling its pathophysiology. We developed a novel mouse model of HCC based on type 1 diabetes and reported its histopathological features.
  
  
  METHODS
  Newborn male ddY, Institute for Animal Reproduction (DIAR) mice were divided into two groups on the basis of streptozotocin treatment, which induces type 1 diabetes. Streptozotocin was subcutaneously injected (60 mg/g) into the treated group (DIAR-nSTZ mice), whereas physiologic solution was injected into the control group (DIAR-control mice) at 1.5 days after birth. All mice were fed a normal diet and histopathologically assessed at 6, 8, 10, 12, 19, and 27 weeks of age.
  
  
  RESULTS
  At 8 weeks, small hepatocytic nodules with mild to moderate cellular atypia were observed in the livers of DIAR-nSTZ mice, which progressed to large hepatocytic nodules with cellular atypia and infiltrating growth at 12 weeks, identical to those in well-differentiated human HCC. At 19 and 27 weeks, moderately differentiated HCC was observed in all DIAR-nSTZ mice. Conversely, no neoplastic findings were evident in DIAR-control mice. No steatosis or fibrosis was evident in either group. Immunohistochemical analysis revealed that all nodules observed in DIAR-nSTZ mice were positive for glutamine synthetase.
  
  
  CONCLUSIONS
  In DIAR-nSTZ mice, the development of HCC with similarity to human HCC and high reproducibility can be achieved using a short and simple protocol. We believe that this model will be useful for studying liver carcinogenesis.
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. hayato.bb@gmail.com.
authors.forename: Hayato
authors.initials: H
authors.lastname: Baba
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. ktsune@med.u-toyama.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. dpnishi@med.u-toyama.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishida
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. hatta@med.u-toyama.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hatta
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. majikana26@hotmail.com.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. knomoto@med.u-toyama.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nomoto
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. g7440004@med.u-toyama.ac.jp.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. miwasige@gmail.com.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Miwa
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. nk24u3@yahoo.co.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakanishi
authors.affiliation: Institute for Animal Reproduction, 1103 Fukaya, Kasumigaura-shi, Ibaraki, 300-0134, Japan. hokao_ryoji@iar.or.jp.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Hokao
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan. imura@med.u-toyama.ac.jp.
authors.forename: Johji
authors.initials: J
authors.lastname: Imura
keywords: Diabetes; Glutamine synthetase; Hepatocellular carcinoma