title: H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance.
abstract: Long noncoding RNA-H19 (H19), an imprinted oncofetal gene, has a central role in carcinogenesis. Hitherto, the mechanism by which H19 regulates cancer stem cells, remains elusive. Here we show that breast cancer stem cells (BCSCs) express high levels of H19, and ectopic overexpression of H19 significantly promotes breast cancer cell clonogenicity, migration and mammosphere-forming ability. Conversely, silencing of H19 represses these BCSC properties. In concordance, knockdown of H19 markedly inhibits tumor growth and suppresses tumorigenesis in nude mice. Mechanistically, we found that H19 functions as a competing endogenous RNA to sponge miRNA let-7, leading to an increase in expression of a let-7 target, the core pluripotency factor LIN28, which is enriched in BCSC populations and breast patient samples. Intriguingly, this gain of LIN28 expression can also feedback to reverse the H19 loss-mediated suppression of BCSC properties. Our data also reveal that LIN28 blocks mature let-7 production and, thereby, de-represses H19 expression in breast cancer cells. Appropriately, H19 and LIN28 expression exhibits strong correlations in primary breast carcinomas. Collectively, these findings reveal that lncRNA H19, miRNA let-7 and transcriptional factor LIN28 form a double-negative feedback loop, which has a critical role in the maintenance of BCSCs. Consequently, disrupting this pathway provides a novel therapeutic strategy for breast cancer.
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Peng
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Wang
authors.affiliation: Department of Breast Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Xiao
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Department of Breast Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
authors.forename: Hai-Dong
authors.initials: HD
authors.lastname: Zhao
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.|Department of Hematology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
authors.forename: Zhi-Jie
authors.initials: ZJ
authors.lastname: Kang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Fan
authors.affiliation: Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zhu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Bai
authors.initials: B
authors.lastname: Cui
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.|Department of Medical Oncology, The Eastern Hospital of The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510700, China.
authors.forename: Fei-Meng
authors.initials: FM
authors.lastname: Zheng
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian 116011, China.
authors.forename: Hong-Jiang
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Department of Medical Oncology, The Eastern Hospital of The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510700, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C094335:H19 long non-coding RNA; C516326:LIN28B protein, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human