Tumor-promoting/progressing role of additional chromosome instability in hepatic carcinogenesis in Sgo1 (Shugoshin 1) haploinsufficient mice.
A major etiological risk factor for hepatocellular carcinoma (HCC) is infection by Hepatitis viruses, especially hepatitis B virus and hepatitis C virus. Hepatitis B virus and hepatitis C virus do not cause aggressive activation of an oncogenic pathway, but they transactivate a broad array of genes, cause chronic inflammation, and, through interference with mitotic processes, lead to mitotic error-induced chromosome instability (ME-CIN). However, how ME-CIN is involved in the development of HCC remains unclear. Delineating the effect of ME-CIN on HCC development should help in identifying measures to combat HCC. In this study, we used ME-CIN model mice haploinsufficient in Shugoshin 1 (Sgo1(-/+)) to assess the role of ME-CIN in HCC development. Treatment with the carcinogen azoxymethane caused Sgo1(-/+) ME-CIN model mice to develop HCCs within 6 months, whereas control mice developed no HCC (P < 0.003). The HCC development was associated with expression of early HCC markers (glutamine synthetase, glypican 3, heat shock protein 70, and the serum marker alpha fetoprotein), although without fibrosis. ME-CIN preceded the expression of HCC markers, suggesting that ME-CIN is an important early event in HCC development. In 12-month-old untreated Sgo1 mice, persistent DNA damage, altered gene expression, and spontaneous HCCs were observed. Sgo1 protein accumulated in response to DNA damage in vitro. Overall, Sgo1(-/+)-mediated ME-CIN strongly promoted/progressed development of HCC in the presence of an initiator carcinogen, and it had a mild initiator effect by itself. Use of the ME-CIN model mice should help in identifying drugs to counteract the effects of ME-CIN and should accelerate anti-HCC drug development.
Center for Cancer Prevention and Drug Development Program, Department of Medicine, Hem/Onc Section, University of Oklahoma Health Sciences Center (OUHSC), 975 NE 10th st. BRC1207, Oklahoma City, Oklahoma 73104 Hiroshi-yamada@ouhsc.edu cv-rao@ouhsc.edu.
Hiroshi Y
HY
Yamada
Center for Cancer Prevention and Drug Development Program, Department of Medicine, Hem/Onc Section, University of Oklahoma Health Sciences Center (OUHSC), 975 NE 10th st. BRC1207, Oklahoma City, Oklahoma 73104.
Yuting
Y
Zhang
Center for Cancer Prevention and Drug Development Program, Department of Medicine, Hem/Onc Section, University of Oklahoma Health Sciences Center (OUHSC), 975 NE 10th st. BRC1207, Oklahoma City, Oklahoma 73104.
Arun
A
Reddy
Center for Cancer Prevention and Drug Development Program, Department of Medicine, Hem/Onc Section, University of Oklahoma Health Sciences Center (OUHSC), 975 NE 10th st. BRC1207, Oklahoma City, Oklahoma 73104.
Altaf
A
Mohammed
Center for Cancer Prevention and Drug Development Program, Department of Medicine, Hem/Onc Section, University of Oklahoma Health Sciences Center (OUHSC), 975 NE 10th st. BRC1207, Oklahoma City, Oklahoma 73104.
Stan
S
Lightfoot
Department of Environmental Medicine, New York University Langone Medical Center, 57 Old Forge Road, Tuxedo, New York 10987.
Wei
W
Dai
Center for Cancer Prevention and Drug Development Program, Department of Medicine, Hem/Onc Section, University of Oklahoma Health Sciences Center (OUHSC), 975 NE 10th st. BRC1207, Oklahoma City, Oklahoma 73104 Hiroshi-yamada@ouhsc.edu cv-rao@ouhsc.edu.
Chinthalapally V
CV
Rao
D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis; D053673:Glypicans / Q000096:biosynthesis; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D057895:Haploinsufficiency / Q000235:genetics; D006367:HeLa Cells; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000472:pathogenicity; D006515:Hepatitis B virus / Q000472:pathogenicity; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis / Q000235:genetics; D000509:alpha-Fetoproteins / Q000096:biosynthesis
D002273:Carcinogens; D018797:Cell Cycle Proteins; C105937:GPC3 protein, human; D053673:Glypicans; D018840:HSP70 Heat-Shock Proteins; D000509:alpha-Fetoproteins; C527733:shugoshin protein, mouse; D005974:Glutamate-Ammonia Ligase; D001397:Azoxymethane