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Oncol Lett. 2018 Nov;16(5):5907-5915. doi: 10.3892/ol.2018.9396. Epub 2018 Sep 4.

A-kinase anchoring protein 12 is downregulated in human hepatocellular carcinoma and its deficiency in mice aggravates thioacetamide-induced liver injury.

Author information

1
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
2
Department of Internal Medicine, Inje University College of Medicine, Seoul Paik Hospital, Seoul 04551, Republic of Korea.
3
Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea.
4
Department of Internal Medicine, Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Seoul 05355, Republic of Korea.
5
Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea.
6
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
7
Crop Biotechnology Institute, Green Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon 25354, Republic of Korea.

Abstract

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 α1 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.

KEYWORDS:

A-kinase anchoring protein 12; hepatocellular carcinoma; liver fibrosis; liver sinusoid; thioacetamide

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