Sulfatide epigenetically regulates miR-223 and promotes the migration of human hepatocellular carcinoma cells

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• 作者：Yi Wei Dong¹ ; Rong Wang¹ ; Qian Qian Cai¹ ; Bing Qi¹ ; Wei Wu¹ ; Yong Hu Zhang² ; Xing Zhong Wu¹ ; ^{xz_wu@shmu.edu.cn" class="auth_mail}
• 关键词：miRNA ; microRNA ; Gal-Cer ; galactocerebroside ; CST ; cerebroside sulfotransferase ; MOZ ; monocytic leukemia zinc finger protein
• 刊名：Journal of Hepatology
• 出版年：April, 2014
• 年：2014
• 卷：60
• 期：4
• 页码：792-801
• 全文大小：3424 K

文摘

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Background & Aims

The biological relevance and regulation mechanism of aberrant miR-223 expression in human hepatocellular carcinoma (HCC) remain unknown. Our aim was to investigate miR-223 regulation in HCC.

Methods

miR-223 and integrin 伪V dysregulation were verified in 57 HCC specimens. Immunohistochemical analysis of integrin 伪V and sulfatide levels was performed on another cohort of 103 HCC samples. Epigenetic analysis was used to explore the effect of sulfatide on miR-223 transcription. Orthotopic growth, and intrahepatic and pulmonary metastasis of tumors derived from SMMC-7721 cells expressing miR-223 or cerebroside sulfotransferase were monitored in mice.

Results

miR-223 was reduced in HCC specimens and highly metastatic cell lines. Enhanced miR-223 expression had a negative effect on integrin 伪V-mediated cell migration. In vivo assays of metastasis in an orthotopically implanted model demonstrated that miR-223 effectively inhibited HCC metastasis. Further analysis demonstrated that integrin 伪V is negatively regulated by miR-223. Moreover, the integrin 伪V subunit was significantly positively correlated with highly expressed sulfatide in 103 HCC specimens. Intriguingly, miR-223 expression was suppressed by sulfatide in HCC in association with reduced recruitment of acetylated histone H3 and C/EBP伪 to the pre-miR-223 gene promoter, where monocytic leukemia zinc finger (MOZ) protein, a MYST-type histone acetyltransferase, lost its attachment. The expression of histone deacetylases, HDAC9 and HDAC10, were greatly stimulated by sulfatide and their recruitment to miR-223 gene promoter was enhanced.

Conclusions

Downregulation of miR-223 in HCC is associated with the epigenetic regulation by highly expressed sulfatide and involved in tumor metastasis.