TY - JOUR
T1 - Hyperglycemia Alters O-GlcNAcylation Patterns of Hepatocytes in Mice Treated with Hepatoxic Carcinogen
AU - Chomphoo, Surang
AU - Kunprom, Waritta
AU - Thithuan, Kanyarat
AU - Sorin, Supannika
AU - Khawkhiaw, Kullanat
AU - Kamkaew, Anyanee
AU - Phoomak, Chatchai
AU - Chiu, Ching Feng
AU - Saengboonmee, Charupong
N1 - Funding Information:
This work was supported by The Fundamental Fund of Khon Kaen University for the year 2565 BE (FF65) with funding support from The National Science, Research, and Innovation Fund (NSRF) of Thailand. We would like to thank Prof. Sopit Wongkham, Department of Biochemistry, Faculty of Medicine, Khon Kaen University, for her guidance and mentoring of the research project under the FF65 grant, and thank Mr. Chitsakul Phuyao, Cholangiocarcinoma Research Institute, Khon Kaen University, for technical help in histological sections. We also acknowledge the contribution of Professor John F. Smith for English editing via the KKU Publication Clinic.
Publisher Copyright:
© 2023 Authors. All rights reserved.
PY - 2023/3
Y1 - 2023/3
N2 - Background/Aim: Diabetes mellitus (DM) is an established risk for hepatocellular carcinoma (HCC), with unclarified mechanisms. This study investigated the effects of hyperglycemia on O-GlcNacylation in hepatocytes and its associations with hepatocarcinogenesis. Materials and Methods: Mouse and human HCC cell lines were used in an in vitro model of hyperglycemia. Western blotting was used to determine the effects of high glucose on O-GlcNacylation in HCC cells. Twenty 4-week-old C3H/HeNJcl mice were randomized into four groups: non-DM control, non-DM plus diethylnitrosamine (DEN), DM, and DM plus DEN. DM was induced using intraperitoneal injection of a single high dose of streptozotocin. DEN was used to induce HCC. All mice were euthanized at week 16 after DM induction, and the liver tissues were histologically examined using hematoxylin and eosin, and immunohistochemistry. Results: High glucose increased O-GlcNacylated proteins in mouse and human HCC cell lines compared with those cultured at normal glucose concentration. Mice with hyperglycemia or DEN treatment had increased O-GlcNacylated proteins in hepatocytes. No gross tumors were evident at the end of the experiment but hepatic morbidity was observed. Mice with hyperglycemia and DEN treatment showed greater histological morbidity in their livers, i.e. increased nuclear size, hepatocellular swelling and sinusoidal dilatation, compared with mice in the DM group or treated with DEN alone. Conclusion: Hyperglycemia increased O-GlcNAcylation in both in vitro and animal models. Increased O-GlcNAcylated proteins may be associated with hepatic histological morbidities which then promote HCC development in carcinogen-induced tumorigenesis.
AB - Background/Aim: Diabetes mellitus (DM) is an established risk for hepatocellular carcinoma (HCC), with unclarified mechanisms. This study investigated the effects of hyperglycemia on O-GlcNacylation in hepatocytes and its associations with hepatocarcinogenesis. Materials and Methods: Mouse and human HCC cell lines were used in an in vitro model of hyperglycemia. Western blotting was used to determine the effects of high glucose on O-GlcNacylation in HCC cells. Twenty 4-week-old C3H/HeNJcl mice were randomized into four groups: non-DM control, non-DM plus diethylnitrosamine (DEN), DM, and DM plus DEN. DM was induced using intraperitoneal injection of a single high dose of streptozotocin. DEN was used to induce HCC. All mice were euthanized at week 16 after DM induction, and the liver tissues were histologically examined using hematoxylin and eosin, and immunohistochemistry. Results: High glucose increased O-GlcNacylated proteins in mouse and human HCC cell lines compared with those cultured at normal glucose concentration. Mice with hyperglycemia or DEN treatment had increased O-GlcNacylated proteins in hepatocytes. No gross tumors were evident at the end of the experiment but hepatic morbidity was observed. Mice with hyperglycemia and DEN treatment showed greater histological morbidity in their livers, i.e. increased nuclear size, hepatocellular swelling and sinusoidal dilatation, compared with mice in the DM group or treated with DEN alone. Conclusion: Hyperglycemia increased O-GlcNAcylation in both in vitro and animal models. Increased O-GlcNAcylated proteins may be associated with hepatic histological morbidities which then promote HCC development in carcinogen-induced tumorigenesis.
KW - Diabetes mellitus
KW - glycosylation
KW - hepatocellular carcinoma
KW - hyperglycemia
KW - O-GlcNacylation
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U2 - 10.21873/invivo.13129
DO - 10.21873/invivo.13129
M3 - Article
C2 - 36881103
AN - SCOPUS:85149544161
SN - 0258-851X
VL - 37
SP - 685
EP - 695
JO - In Vivo
JF - In Vivo
IS - 2
ER -
