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Transcriptional regulation of miR-224 upregulated in human HCCs by NFκB inflammatory pathways.

Abstract：

BACKGROUND & AIMS:miR-224 is up-regulated in human HCCs as compared to both paired peri-tumoral cirrhotic tissues and cirrhotic livers without HCC. Here, we have cloned the miR-224 regulatory region and characterized its transcriptional regulation by the NFκB-dependent inflammatory pathways. METHODS:Mature miRNA expression was evaluated by a 2 step stem-loop real-time RT-PCR. The recruitment of polymerase II and transcription factors on the pre-miR-224 promoter has been assessed by ChIPSeq and ChIP. RESULTS:We found miR-224 levels strongly up-regulated in both peri-tumoral cirrhotic livers and HCC samples as compared to normal livers. In silico analysis of the putative miR-224 promoter revealed multiple NFκB sites. We showed that LTα and TNFα activate transcription from the miR-224 promoter and of endogenous miR-224 expression in HCC cell lines, whereas the expression of miR-224 target API5 was reduced. Exogenously expressed p65/RelA activates the miR-224 promoter and a dominant negative form of IκBα (IκBSR) represses it. ChIP analysis showed that p65/NFκB is recruited on the miR-224 promoter and that its binding sharply increases after exposure to LPS, TNFα, and LTα. Altogether these findings link the inflammatory signals to NFκB-mediated activation of miR-224 expression. An antago-miR specific for miR-224 blocked LPS and LTα stimulated HCC cells migration and invasion. Conversely, the IKK inhibitor BMS-345541 blocks pre-miR-224-induced cellular migration and invasion. CONCLUSIONS:Our results identify p65/NFκB as a direct transcriptional regulator of miR-224 expression and link miR-224 up-regulation with the activation of the LPS, LTα, and TNFα inflammatory pathways and cell migration/invasion in HCC.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Scisciani C,Vossio S,Guerrieri F,Schinzari V,De Iaco R,D'Onorio de Meo P,Cervello M,Montalto G,Pollicino T,Raimondo G,Levrero M,Pediconi N

doi

10.1016/j.jhep.2011.11.017

subject

Has Abstract

pub_date

2012-04-01 00:00:00

pages

855-61

issue

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(11)00870-1

journal_volume

pub_type

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Transcriptional regulation of miR-224 upregulated in human HCCs by NFκB inflammatory pathways.