Down-Regulation of Tumor Suppressor A Kinase Anchor Protein 12 in Human Hepatocarcinogenesis by Epigenetic Mechanisms

作者：Goeppert Benjamin^*; Schmezer Peter; Dutruel Celine; Oakes Christopher; Renner Marcus; Breinig Marco; Warth Arne; Vogel Monika Nadja; Mittelbronn Michel; Mehrabi Arianeb; Gdynia Georg; Penzel Roland; Longerich Thomas; Breuhahn Kai; Popanda Odilia; Plass Christoph; Schirmacher Peter; Kern Michael Andre

来源：Hepatology, 2010, 52(6): 2023-2033.

DOI：10.1002/hep.23939

The A kinase anchor protein 12 (AKAP12) is a central mediator of protein kinase A and protein kinase C signaling Although AKAP12 has been described to act as a tumor suppressor and its expression is frequently down-regulated in several human malignancies, the underlying molecular mechanisms responsible for the AKAP12 reduction are poorly understood We therefore analyzed the expression of AKAP12 and its genetic and epigenetic regulatory mechanisms in human hepatocarcinogenesis Based on tissue microarray analyses (n = 388) and western immunoblotting, we observed a significant reduction of AKAP12 in cirrhotic liver (CL), premalignant lesions (DN), and hepatocellular carcinomas (HCCs) compared to histologically normal liver specimens (NL) Analyses of array comparative genomic hybridization data (aCGH) from human HCCs revealed chromosomal losses of AKAP12 in 36% of cases but suggested additional mechanisms underlymg the observed reduction of AKAP12 expression in hepatocarcinogenesis Quantitative methylation analysis by MassARRAY of NL, CL, DN, and HCC tissues, as well as of various tumorigenic and nontumorigenic liver cell lines revealed specific hypermethylation of the AKAP12 alpha promoter but not of the AKAP12 beta promoter in HCC specimens and in HCC cell lines Consequently, restoration experiments performed with 5-aza-2'deoxycytidine drastically increased AKAP12a mRNA levels in a HCC cell line (AKN1) paralleled by AKAP12 alpha promoter demethylation As hypermethylation is not observed in CL and DN, we investigated microRNA-mediated posttranscriptional regulation as an additional mechanism to explain reduced AKAP12 expression We found that miR-183 and miR-186 are up-regulated in CL and DN and are able to target AKAP12 Conclusion In addition to genetic alterations, epigenetic mechanisms are responsible for the reduction of the tumor suppressor gene AKAP12 in human hepatocarcinogenesis (HEPATOLOGY 2010,52 2023-2034)

• 出版日期2010-12