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H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance

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Title: H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance
Authors: Peng, F
Li, TT
Wang, KL
Xiao, GQ
Wang, JH
Zhao, HD
Kang, ZJ
Fan, WJ
Zhu, LL
Li, M
Cui, B
Zheng, FM
Wang, HJ
Lam, EW
Wang, B
Xu, J
Liu, Q
Item Type: Journal Article
Abstract: LincRNA-H19 ( H19 ), an imprinted oncofetal gene, plays a central role in carcinogenesis. Hitherto, the mechanism by which H19 regulates cancer stem cells (CSCs) 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 ma mmosphere-forming ability. Conversely, silencing of H19 represses these BCSC properties. In concordance, knockdown of H19 dramatically inhibits tumor growth an d suppresses tumorigenesis in nude mice. Mechanistically, we found that H19 functions as a competing endogenous RNA (ceRNA) to sponge miRNA let-7, leading to an increase in expression of a let-7 target, the core pluripotency factor LIN28, wh ich is enriched in BCSC populations and breast patient samples. Intriguingly, this gain of LIN28 expression can also feedback to reverse the H19 loss-mediated suppre ssion 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 carcino mas. Collectively, these findings reveal that lincRNA H19, miRNA let-7 and transcriptional factor LIN28 form a double negative feedback loop, which plays a cr itical role in the maintenance of BCSCs. Consequently, disrupting this pathway provid es a novel therapeutic strategy for breast cancer.
Issue Date: 19-Jan-2017
Date of Acceptance: 25-Nov-2016
URI: http://hdl.handle.net/10044/1/42735
DOI: https://dx.doi.org/10.1038/cddis.2016.438
ISSN: 2041-4889
Publisher: Nature Publishing Group
Journal / Book Title: Cell Death & Disease
Volume: 8
Copyright Statement: © The Author(s) 2017Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Cancer Research UK
Breast Cancer Now
Breast Cancer Campaign and Breakthrough Breast Cancer
Funder's Grant Number: C37/A12011
Publication Status: Published
Article Number: e2569
Appears in Collections:Department of Surgery and Cancer