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

Lee,Hye Shin; Choi,Jinhyeok; Son,Taekwon; Lee,Eun Ji; Kim,Jeong‑Gyun; Ryu,Soo Hyung; Lee,Danbi; Jang,Myoung Kuk; Yu,Eunsil; Chung,Young‑Hwa; Gelman,Irwin H.; Kim,Kyu‑Won

doi:10.3892/ol.2018.9396

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

Authors:
- Hye Shin Lee
- Jinhyeok Choi
- Taekwon Son
- Eun Ji Lee
- Jeong‑Gyun Kim
- Soo Hyung Ryu
- Danbi Lee
- Myoung Kuk Jang
- Eunsil Yu
- Young‑Hwa Chung
- Irwin H. Gelman
- Kyu‑Won Kim
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Affiliations: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea, Department of Internal Medicine, Inje University College of Medicine, Seoul Paik Hospital, Seoul 04551, Republic of Korea, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea, Department of Internal Medicine, Hallym University College of Medicine, Kangdong Sacred Heart Hospital, Seoul 05355, Republic of Korea, Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea, Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
Published online on: September 4, 2018 https://doi.org/10.3892/ol.2018.9396
Pages: 5907-5915
Copyright: © Lee et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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1	Pellicoro A, Ramachandran P, Iredale JP and Fallowfield JA: Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat Rev Immunol. 14:181–194. 2014. View Article : Google Scholar : PubMed/NCBI
2	Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 134:1655–1669. 2008. View Article : Google Scholar : PubMed/NCBI
3	Sakurai T and Kudo M: Molecular link between liver fibrosis and hepatocellular carcinoma. Liver Cancer. 2:365–366. 2013. View Article : Google Scholar : PubMed/NCBI
4	Fausther M, Pritchard MT, Popov YV and Bridle K: Contribution of liver nonparenchymal cells to hepatic fibrosis: Interactions with the local microenvironment. Biomed Res Int. 2017:68247622017. View Article : Google Scholar : PubMed/NCBI
5	Carnegie GK, Means CK and Scott JD: A-kinase anchoring proteins: From protein complexes to physiology and disease. IUBMB Life. 61:394–406. 2009. View Article : Google Scholar : PubMed/NCBI
6	Poppinga WJ, Muñoz-Llancao P, Gonzalez-Billault C and Schmidt M: A-kinase anchoring proteins: cAMP compartmentalization in neurodegenerative and obstructive pulmonary diseases. Br J Pharmacol. 171:5603–5623. 2014. View Article : Google Scholar : PubMed/NCBI
7	Gelman IH: Suppression of tumor and metastasis progression through the scaffolding functions of SSeCKS/Gravin/AKAP12. Cancer Metastasis Rev. 31:493–500. 2012. View Article : Google Scholar : PubMed/NCBI
8	Lee SW, Kim WJ, Choi YK, Song HS, Son MJ, Gelman IH, Kim YJ and Kim KW: SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med. 9:900–906. 2003. View Article : Google Scholar : PubMed/NCBI
9	Liu W, Gong J, Hu J, Hu T, Sun Y, Du J, Sun C, Guan M, Jiang H and Lu Y: Quantitative assessment of AKAP12 promoter methylation in human prostate cancer using methylation-sensitive high-resolution melting: Correlation with gleason score. Urology. 77(1006): e1–7. 2011.PubMed/NCBI
10	Akakura S, Huang C, Nelson PJ, Foster B and Gelman IH: Loss of the SSeCKS/Gravin/AKAP12 gene results in prostatic hyperplasia. Cancer Res. 68:5096–5103. 2008. View Article : Google Scholar : PubMed/NCBI
11	Gelman IH: The role of SSeCKS/gravin/AKAP12 scaffolding proteins in the spaciotemporal control of signaling pathways in oncogenesis and development. Front Biosci. 7:d1782–d1797. 2002. View Article : Google Scholar : PubMed/NCBI
12	Choi MC, Jong HS, Kim TY, Song SH, Lee DS, Lee JW, Kim TY, Kim NK and Bang YJ: AKAP12/Gravin is inactivated by epigenetic mechanism in human gastric carcinoma and shows growth suppressor activity. Oncogene. 23:7095–7103. 2004. View Article : Google Scholar : PubMed/NCBI
13	Xia W, Unger P, Miller L, Nelson J and Gelman IH: The Src-suppressed C kinase substrate, SSeCKS, is a potential metastasis inhibitor in prostate cancer. Cancer Res. 61:5644–5651. 2001.PubMed/NCBI
14	Lin X and Gelman IH: Reexpression of the major protein kinase C substrate, SSeCKS, suppresses v-src-induced morphological transformation and tumorigenesis. Cancer Res. 57:2304–2312. 1997.PubMed/NCBI
15	Goeppert B, Schmezer P, Dutruel C, Oakes C, Renner M, Breinig M, Warth A, Vogel MN, Mittelbronn M, Mehrabi A, et al: Down-regulation of tumor suppressor A kinase anchor protein 12 in human hepatocarcinogenesis by epigenetic mechanisms. Hepatology. 52:2023–2033. 2010. View Article : Google Scholar : PubMed/NCBI
16	Hayashi M, Nomoto S, Kanda M, Okamura Y, Nishikawa Y, Yamada S, Fujii T, Sugimoto H, Takeda S and Kodera Y: Identification of the A kinase anchor protein 12 (AKAP12) gene as a candidate tumor suppressor of hepatocellular carcinoma. J Surg Oncol. 105:381–386. 2012. View Article : Google Scholar : PubMed/NCBI
17	Xia W, Ni J, Zhuang J, Qian L, Wang P and Wang J: MiR-103 regulates hepatocellular carcinoma growth by targeting AKAP12. Int J Biochem Cell Biol. 71:1–11. 2016. View Article : Google Scholar : PubMed/NCBI
18	Liu Y, Meyer C, Xu C, Weng H, Hellerbrand C, ten Dijke P and Dooley S: Animal models of chronic liver diseases. Am J Physiol Gastrointest Liver Physiol. 304:G449–G468. 2013. View Article : Google Scholar : PubMed/NCBI
19	Wallace MC, Hamesch K, Lunova M, Kim Y, Weiskirchen R, Strnad P and Friedman SL: Standard operating procedures in experimental liver research: Thioacetamide model in mice and rats. Lab Anim. 49 1 Suppl:S21–S29. 2015. View Article : Google Scholar
20	Abe M, Yoshida T, Akiba J, Ikezono Y, Wada F, Masuda A, Sakaue T, Tanaka T, Iwamoto H, Nakamura T, et al: STAT3 deficiency prevents hepatocarcinogenesis and promotes biliary proliferation in thioacetamide-induced liver injury. World J Gastroenterol. 23:6833–6844. 2017. View Article : Google Scholar : PubMed/NCBI
21	Hartig SM: Basic image analysis and manipulation in ImageJ. Curr Protoc Mol Biol Chapter. 14:Unit14 15. 2013.doi: 10.1002/0471142727.mb1415s102. View Article : Google Scholar
22	Shin MW, Bae SJ, Wee HJ, Lee HJ, Ahn BJ, Le H, Lee EJ, Kim RH, Lee HS, Seo JH, et al: Ninjurin1 regulates lipopolysaccharide-induced inflammation through direct binding. Int J Oncol. 48:821–828. 2016. View Article : Google Scholar : PubMed/NCBI
23	Sakurai T, Yada N, Watanabe T, Arizumi T, Hagiwara S, Ueshima K, Nishida N, Fujita J and Kudo M: Cold-inducible RNA-binding protein promotes the development of liver cancer. Cancer Sci. 106:352–358. 2015. View Article : Google Scholar : PubMed/NCBI
24	Helmy SA, El-Mesery M, El-Karef A, Eissa LA and El Gayar AM: Chloroquine upregulates TRAIL/TRAILR2 expression and potentiates doxorubicin anti-tumor activity in thioacetamide-induced hepatocellular carcinoma model. Chem Biol Interact. 279:84–94. 2018. View Article : Google Scholar : PubMed/NCBI
25	Balkwill FR, Capasso M and Hagemann T: The tumor microenvironment at a glance. J Cell Sci. 125:5591–5596. 2012. View Article : Google Scholar : PubMed/NCBI
26	Hanahan D and Coussens LM: Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell. 21:309–322. 2012. View Article : Google Scholar : PubMed/NCBI
27	Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C and Marini FC: Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res. 18:842016. View Article : Google Scholar : PubMed/NCBI
28	Campbell I, Qiu W and Haviv I: Genetic changes in tumour microenvironments. J Pathol. 223:450–458. 2011. View Article : Google Scholar : PubMed/NCBI
29	Fukino K, Shen L, Patocs A, Mutter GL and Eng C: Genomic instability within tumor stroma and clinicopathological characteristics of sporadic primary invasive breast carcinoma. JAMA. 297:2103–2111. 2007. View Article : Google Scholar : PubMed/NCBI
30	Wernert N, Löcherbach C, Wellmann A, Behrens P and Hügel A: Presence of genetic alterations in microdissected stroma of human colon and breast cancers. Anticancer Res. 21:2259–2264. 2001.PubMed/NCBI
31	Arriazu E, de Galarreta Ruiz M, Cubero FJ, Varela-Rey M, de Obanos Pérez MP, Leung TM, Lopategi A, Benedicto A, Abraham-Enachescu I and Nieto N: Extracellular matrix and liver disease. Antioxid Redox Signal. 21:1078–1097. 2014. View Article : Google Scholar : PubMed/NCBI