Hicago, IL 60612, USA 3 Division of Digestive Diseases, Department of Internal Medicine, Rush University Medical Center, 1725 West Harrison, Suite 206, Chicago, IL 60612, USA?The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Guo et al. Clinical Epigenetics (2017) 9:116 DOI 10.1186/s13148-017-0412-RESEARCHOpen AccessSilencing HOXD10 by promoter region hypermethylation activates ERK signaling in hepatocellular carcinomaYulin Guo1,2, Yaojun Peng1, Dan Gao1,3, Meiying Zhang1,3, Weili Yang1,3, Enqiang Linghu1, James G. Herman4, Fran is Fuks5, Guanglong Dong2* and Mingzhou Guo1*AbstractBackground: Hepatocellular carcinoma is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Dysregulation of HomeoboxD10 (HOXD10) was found to suppress or promote cancer progression in different cancer types. The function and regulation of HOXD10 remain unclear in human hepatocellular carcinoma (HCC). Methods: Primary HCC samples (117), normal liver tissue samples (15), and 13 HCC cell lines (SNU182, SNU449, HBXF344, SMMC7721, Huh7, HepG2, LM3, PLC/PRF/5, BEL7402, SNU387, SNU475, QGY7703, and Huh1) were included in this study. Methylation-specific PCR, flow cytometry, western blot, transwell, siRNA, and chromatin immunoprecipitation assays were employed. Results: HOXD10 was methylated in 76.9 (90/117) of human primary HCC samples. HOXD10 methylation was significantly associated with vessel cancerous embolus, tumor cell differentiation, and the 3-year overall survival rate (all P < 0.05). The expression of HOXD10 was regulated by promoter region methylation. HOXD10 suppressed colony formation, cell proliferation, cell invasion and migration, and induced G2/M phase arrest and apoptosis in HCC cells. HOXD10 suppressed HCC cell xenograft growth in mice. HOXD10 suppresses HCC growth by inhibiting ERK signaling. Conclusion: HOXD10 is frequently methylated in human HCC, and the expression of HOXD10 is regulated by promoter region methylation. HOXD10 suppresses HCC cell growth both in vitro and in vivo. HOXD10 suppresses human HCC by inhibiting ERK signaling. Keywords: HOXD10, DNA methylation, Hepatocellular carcinoma, IGFBP3, ERK1/Background Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer-related death worldwide [1]. In China, HCC is the fourth most commonly diagnosed cancer in men, and it is the third leading cause of cancer death for both men and women [2]. The PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28945807 5-year survival rate remains below 12 [3]. The get Zebularine mechanisms underlying the development and* Correspondence: [email protected]; [email protected] Equal contributors 2 Department of General Surgery, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China 1 Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing 100853, China Full list of author information is available at the end of the articleprogression of HC.