Journal
ONCOLOGY LETTERS
Volume 16, Issue 5, Pages 5907-5915Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ol.2018.9396
Keywords
liver fibrosis; hepatocellular carcinoma; thioacetamide; A-kinase anchoring protein 12; liver sinusoid
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Funding
- Global Core Research Center (GCRC) Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Ministry of Science, ICT and Future Planning (MSIP) [2011-00,30001]
- Bio & Medical Technology Development Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Ministry of Science, ICT and Future Planning (MSIP) [2015M3A9E6028949]
- NRF grant through the National Research Foundation of Korea (NRF) - Ministry of Education, Ministry of Science, ICT and Future Planning (MSIP) [2015R1C1A2A01054446]
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AKAP12 belongs to A-kinase anchoring protein (AKAP) family of scaffold proteins and is known as a tumor suppressor in several human cancer types. Its role as a tumor suppressor in hepatocellular carcinoma (HCC) was proposed due to its downregulation and epigenetic modification in human HCC; however, the effect of its deficiency on liver injuries, such as liver fibrosis and cancer has been poorly studied. By analyzing tumor and non-tumor tissues of 15 patients with HCC, it was confirmed that AKAP12 expression was downregulated in human HCC as compared with adjacent non-tumor tissues. Immunohistochemical staining of mouse liver tissue for AKAP12 revealed that its sinusoidal expression was diminished in capillarized endothelium after 8 weeks of thioacetamide (TAA) administration. AKAP12 deficiency resulted in the promotion of ductular response of biliary epithelial cells, whereas overall fibrosis and myofibroblast activation were comparable between genotypes after short-term TAA treatment. The mRNA expressions of some fibrosis-related genes such as those encoding epithelial cell adhesion molecule, collagen type 1 1 and elastin were upregulated in liver tissues of AKAP12-knockout mice. Long-term administration of TAA for 26 weeks led to the development of liver tumors; the incidence of tumor development was higher in AKAP12-deficient mice than in wild-type littermates. Together, these results suggest that AKAP12 functions as a tumor suppressor in liver cancer and is associated with the regulation of hepatic non-parenchymal cells.
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