启动子区域高甲基化沉默 HOXD10 激活肝癌中的 ERK 信号通路。
Silencing HOXD10 by promoter region hypermethylation activates ERK signaling in hepatocellular carcinoma.
机构信息
Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China.
Department of General Surgery, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China.
出版信息
Clin Epigenetics. 2017 Oct 23;9:116. doi: 10.1186/s13148-017-0412-9. eCollection 2017.
BACKGROUND
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 < 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.
背景
肝细胞癌是全球第五大常见恶性肿瘤，也是癌症相关死亡的第三大主要原因。在不同类型的癌症中，同源盒蛋白 D10（HOXD10）的失调被发现可抑制或促进癌症进展。HOXD10 在人肝细胞癌（HCC）中的功能和调控仍不清楚。
方法
本研究纳入了 117 例原发性 HCC 样本、15 例正常肝组织样本和 13 株 HCC 细胞系（SNU182、SNU449、HBXF344、SMMC7721、Huh7、HepG2、LM3、PLC/PRF/5、BEL7402、SNU387、SNU475、QGY7703 和 Huh1）。采用甲基化特异性 PCR、流式细胞术、western blot、Transwell、siRNA 和染色质免疫沉淀实验进行检测。
结果
在 76.9%（90/117）的人原发性 HCC 样本中，HOXD10 发生甲基化。HOXD10 甲基化与血管癌栓、肿瘤细胞分化和 3 年总生存率显著相关（均<0.05）。HOXD10 的表达受启动子区域甲基化调控。HOXD10 可抑制 HCC 细胞集落形成、增殖、侵袭和迁移，并诱导 HCC 细胞 G2/M 期阻滞和凋亡。HOXD10 可抑制 HCC 细胞在小鼠中的异种移植生长。HOXD10 通过抑制 ERK 信号通路抑制 HCC 细胞生长。
结论
HOXD10 在人 HCC 中经常发生甲基化，HOXD10 的表达受启动子区域甲基化调控。HOXD10 在体外和体内均能抑制 HCC 细胞生长。HOXD10 通过抑制 ERK 信号通路抑制人 HCC 的生长。
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