H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance
File(s)
Published version
Author(s)
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.
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.
Date Issued
2017-01-19
Date Acceptance
2016-11-25
Citation
Cell Death & Disease, 2017, 8
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
Cancer Research UK
Breast Cancer Now
Breast Cancer Campaign and Breakthrough Breast Cancer
Grant Number
C37/A12011
2012NovemberPhD016
2012MayPR070
Publication Status
Published
Article Number
e2569