title: PBX3 is targeted by multiple miRNAs and is essential for liver tumour-initiating cells.
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.
authors.affiliation: Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing 100142, China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Han
authors.affiliation: Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing 100142, China.
authors.forename: Yantao
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing 100142, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing 100142, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing 100142, China.
authors.forename: Dongji
authors.initials: D
authors.lastname: Chen
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, Oslo University Hospital, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0379, Norway.
authors.forename: Zhenhe
authors.initials: Z
authors.lastname: Suo
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xiuwu
authors.initials: X
authors.lastname: Bian
authors.affiliation: Department of Hepatobiliary Surgery I, Peking University Cancer Hospital and Institute, Beijing 100142, China.
authors.forename: Baocai
authors.initials: B
authors.lastname: Xing
authors.affiliation: Department of Cell Biology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center for Molecular and Translational Medicine, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Beijing 100142, China.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D018398:Homeodomain Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C425903:CACNA2D1 protein, human; C533896:MIRN200 microRNA, human; C525710:MIR222, human; C554214:MIRN424 microrna, human; C487931:mirnlet7 microRNA, human; C090466:proto-oncogene protein Pbx3