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Oncol Lett. 2015 Oct;10(4):2227-2232. Epub 2015 Aug 4.

BRD4 induces cell migration and invasion in HCC cells through MMP-2 and MMP-9 activation mediated by the Sonic hedgehog signaling pathway.

Author information

1
Department of General Surgery, The Affiliated Zhongda Hospital, Medical School, Southeast University, Nanjing 210096, P.R. China.
2
Radiotherapy Department of Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China.
3
Emergency Department of Weifang Traditional Chinese Hospital, Weifang, Shandong 261041, P.R. China.
4
Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing 210096, P.R. China.

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive form of carcinoma with poor prognosis, and HCC-associated mortality primarily occurs due to migration and invasion of HCC cells. The manipulation of epigenetic proteins, such as BRD4, has recently emerged as an alternative therapeutic strategy. The present study aimed to investigate the novel mechanism of BRD4 involvement in the migration and invasion of HCC cells. Reverse transcription-quantitative polymerase chain reaction was used to assess BRD4 mRNA expression levels in HCC cell lines. This analysis demonstrated that BRD4 was significantly overexpressed in HCC cell lines compared with a human immortalized normal liver cell line. A short hairpin RNA (shRNA) was then used to suppress BRD4 expression in HCC cells, and resulted in impaired HCC cell proliferation, migration and invasion. When the HepG2 HCC cell line was treated with recombinant human sonic hedgehog (SHH) peptide, the migration and invasion capabilities of HepG2 cells that were inhibited by BRD4 silencing were restored. BRD4 induced cell migration and invasion in HepG2 cells through the activation of matrix metalloproteinase (MMP)-2 and MMP-9, mediated by the SHH signaling pathway. Taken together, the results of the present study demonstrated the importance of BRD4 in HCC cell proliferation and metastasis. Thus, BRD4 is a potential novel target for the development of therapeutic approaches against HCC.

KEYWORDS:

BRD4; hepatocellular carcinoma; matrix metalloproteinase; migration and invasion; sonic hedgehog pathway

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