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Neonatal streptozotocin treatment causes type 1 diabetes and subsequent hepatocellular carcinoma in DIAR mice fed a normal diet

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Abstract

Purpose

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.

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Acknowledgements

We thank Tokimasa Kumada, Mitsuko Sutoh, and Emu Oda for their help and technical assistance with our experiments. We would also like to thank Yukari Inoue for her excellent support during the preparation of this manuscript. This work was supported by JSPS KAKENHI grant nos. 0293341 and 10293341.

Compliance with ethical requirements and Conflict of interest

Animal care and surgical procedures were approved by the Institute of Animal Reproduction in accordance with criteria outlined in the “Principles of laboratory animal care” prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication no. 85-23 revised 1985). Hayato Baba, Koichi Tsuneyama, Takeshi Nishida, Hideki Hatta, Takahiko Nakajima, Kazuhiro Nomoto, Shinichi Hayashi, Shigeharu Miwa, Yuko Nakanishi, Ryoji Hokao, and Johji Imura1 declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan

    Hayato Baba, Koichi Tsuneyama, Takeshi Nishida, Hideki Hatta, Takahiko Nakajima, Kazuhiro Nomoto, Shinichi Hayashi, Shigeharu Miwa, Yuko Nakanishi & Johji Imura

  2. Institute for Animal Reproduction, 1103 Fukaya, Kasumigaura-shi, Ibaraki, 300-0134, Japan

    Ryoji Hokao

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  1. Hayato Baba
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Correspondence to Koichi Tsuneyama.

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Baba, H., Tsuneyama, K., Nishida, T. et al. Neonatal streptozotocin treatment causes type 1 diabetes and subsequent hepatocellular carcinoma in DIAR mice fed a normal diet. Hepatol Int 8, 415–424 (2014). https://doi.org/10.1007/s12072-014-9541-9

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  • DOI: https://doi.org/10.1007/s12072-014-9541-9

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