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ID 118286
Title Alternative
新生仔期におけるストレプトゾトシン投与は、標準食摂取下の4CSマウスにおいて、持続的な高血糖を伴わずに異なるサブタイプの肝細胞癌を急速に引き起こす
Author
Kobayashi, Tomoko Tokushima University
Morimoto, Yuki Tokushima University
Sumida, Satoshi Tokushima University
Kakimoto, Takumi Tokushima University
Sutoh, Mitsuko Institute for Animal Reproduction
Toyohara, Shunji Institute for Animal Reproduction
Hokao, Ryoji Institute for Animal Reproduction
Cheng, Chunmei Novo Nordisk Research Centre
Keywords
Animal model
Hyperglycemia
Hepatocellular carcinoma
HCC subclasses
Streptozotocin
Content Type
Thesis or Dissertation
Description
Although diabetes mellitus (DM) is a well-known risk factor for hepatocellular carcinoma (HCC), the underlying mechanisms have not yet to be defined. We previously reported that DIAR mice fed with standard murine diet developed type 1 diabetes and HCC at age of 16 weeks old with a neonatal streptozotocin treatment (n-STZ). Because DIAR mice did not manifest obesity nor develop steatohepatitis, hyperglycemia with streptozotocin trigger or streptozotocin alone might turn on the hepato-carcinogenesis. An insulin-recruitment to DIAR-nSTZ mice showed an increased frequency of HCC during the first 12 weeks of age, although the diabetic indications notably improved. To elucidate the role of hyperglycemia in hepato-carcinogenesis, we performed a head-to-head comparative study by using 4CS mice and DIAR mice with n-STZ treatment. Newborn 4CS mice and DIAR mice were divided into STZ treated group and control group. The blood glucose levels of DIAR-nSTZ mice increased at age of eight weeks, while that of 4CS-nSTZ mice were maintained in the normal range. At eight weeks old, three out of five DIAR-nSTZ mice (60%) and one out of ten 4CS-nSTZ mice (10%) developed multiple liver tumors. At age of 12 weeks old, all eight of DIAR-nSTZ mice (100%) and two of 10 4CS-nSTZ mice (20%) developed multiple liver tumors. At 16 weeks old, all animals of DIAR-nSTZ and 4CS-nSTZ mice occurred liver tumors. DIAR-nSTZ showed hyperglycemia and HCC, and 4CS-nSTZ developed HCC without hyperglycemia. These results were interpreted that the onset of HCC maybe not related to the presence or absence of hyperglycemia but nSTZ treatment. On the other hand, since the carcinogenesis of 4CS-nSTZ is delayed compared to DIAR-nSTZ, hyperglycemia may play a role in the progression of carcinogenesis. Histologically, the liver tumor appeared irregularly trabecular arrangements of hepatocytes with various degrees of nuclear atypia. By immunohistochemical analyses, all liver tumors showed positive staining of glutamine synthetase (GS), an established human HCC marker. The expression pattern of GS was divided into a strong diffuse pattern and weak patchy pattern, respectively. The liver tumor showing the weak GS-patchy pattern expressed biliary/stem markers, EpCAM, and SALL4, partially. Because 4CS-nSTZ mice did not show any metabolic complications such as gaining body weight or high blood glucose level, it is a unique animal model with a simple condition to investigate hepatic carcinogenesis by excluding other factors.
Journal Title
Pathology - Research and Practice
ISSN
03440338
16180631
NCID
AA00769966
AA1208415X
Publisher
Elsevier
Volume
225
Start Page
153559
Published Date
2021-07-21
Remark
内容要旨・審査要旨・論文本文の公開
本論文は,著者Tomoko Kobayashiの学位論文として提出され,学位審査・授与の対象となっている。
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3695号
Diploma Number
甲医第1564号
Granted Date
2023-03-23
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Medical Sciences