PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells

Haibo Han, Yantao Du, Wei Zhao, Sheng Li, Dongji Chen, Jing Zhang, Jiang Liu, Zhenhe Suo, Xiuwu Bian, Baocai Xing and Zhiqian Zhang ()
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Haibo Han: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute
Yantao Du: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute
Wei Zhao: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute
Sheng Li: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute
Dongji Chen: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute
Jing Zhang: Beijing Institute of Genomics, Chinese Academy of Sciences
Jiang Liu: Beijing Institute of Genomics, Chinese Academy of Sciences
Zhenhe Suo: Oslo University Hospital, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo
Xiuwu Bian: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University
Baocai Xing: Peking University Cancer Hospital and Institute
Zhiqian Zhang: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: Abstract Tumour-initiating cells (TICs) are advocated to constitute the sustaining force to maintain and renew fully established malignancy; however, the molecular mechanisms responsible for these properties are elusive. We previously demonstrated that voltage-gated calcium channel α2δ1 subunit marks hepatocellular carcinoma (HCC) TICs. Here we confirm directly that α2δ1 is a HCC TIC surface marker, and identify let-7c, miR-200b, miR-222 and miR-424 as suppressors of α2δ1+ HCC TICs. Interestingly, all the four miRNAs synergistically target PBX3, which is sufficient and necessary for the acquisition and maintenance of TIC properties. Moreover, PBX3 drives an essential transcriptional programme, activating the expression of genes critical for HCC TIC stemness including CACNA2D1, EpCAM, SOX2 and NOTCH3. In addition, the expression of CACNA2D1 and PBX3 mRNA is predictive of poor prognosis for HCC patients. Collectively, our study identifies an essential signalling pathway that controls the switch of HCC TIC phenotypes.

Date: 2015
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DOI: 10.1038/ncomms9271

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