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.