MicroRNA122 is a key regulator of α-fetoprotein expression and influences the aggressiveness of hepatocellular carcinoma

Kentaro Kojima, Akemi Takata, Charles Vadnais, Motoyuki Otsuka (), Takeshi Yoshikawa, Masao Akanuma, Yuji Kondo, Young Jun Kang, Takahiro Kishikawa, Naoya Kato, Zhifang Xie, Weiping J. Zhang, Haruhiko Yoshida, Masao Omata, Alain Nepveu and Kazuhiko Koike
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Kentaro Kojima: Graduate School of Medicine, The University of Tokyo
Akemi Takata: Graduate School of Medicine, The University of Tokyo
Charles Vadnais: Biochemistry and Medicine, McGill University
Motoyuki Otsuka: Graduate School of Medicine, The University of Tokyo
Takeshi Yoshikawa: Graduate School of Medicine, The University of Tokyo
Masao Akanuma: The Institute for Adult Diseases, Asahi Life Foundation
Yuji Kondo: Graduate School of Medicine, The University of Tokyo
Young Jun Kang: The Scripps Research Institute
Takahiro Kishikawa: Graduate School of Medicine, The University of Tokyo
Naoya Kato: Unit of Disease Control Genome Medicine, The Institute of Medical Science, The University of Tokyo
Zhifang Xie: Second Military Medical University
Weiping J. Zhang: Second Military Medical University
Haruhiko Yoshida: Graduate School of Medicine, The University of Tokyo
Masao Omata: Graduate School of Medicine, The University of Tokyo
Alain Nepveu: Biochemistry and Medicine, McGill University
Kazuhiko Koike: Graduate School of Medicine, The University of Tokyo

Nature Communications, 2011, vol. 2, issue 1, 1-11

Abstract: Abstract α-fetoprotein (AFP) is not only a widely used biomarker in hepatocellular carcinoma (HCC) surveillance, but is also clinically recognized as linked with aggressive tumour behaviour. Here we show that deregulation of microRNA122, a liver-specific microRNA, is a cause of both AFP elevation and a more biologically aggressive phenotype in HCC. We identify CUX1, a direct target of microRNA122, as a common central mediator of these two effects. Using liver tissues from transgenic mice in which microRNA122 is functionally silenced, an orthotopic xenograft tumour model, and human clinical samples, we further demonstrate that a microRNA122/CUX1/microRNA214/ZBTB20 pathway regulates AFP expression. We also show that the microRNA122/CUX1/RhoA pathway regulates the aggressive characteristics of tumours. We conclude that microRNA122 and associated signalling proteins may represent viable therapeutic targets, and that serum AFP levels in HCC patients may be a surrogate marker for deregulated intracellular microRNA122 signalling pathways in HCC tissues.

Date: 2011
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DOI: 10.1038/ncomms1345

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