Journal
CELL DEATH & DISEASE
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-018-1077-9
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Funding
- Innovative Research Team in University of Ministry of Education of China [IRT_ 17R15]
- National Natural Science Foundation of China [81630005, 81573025, 81402445, 81402071, 81502579, 81502594, 81602585, 81703062, 81703091]
- Dalian high-level talent innovation program [2016RD12]
- MRC [MR/N012097/1]
- CRUK [A12011]
- Breast Cancer Now [2012MayPR070, 2012NovPhD016]
- International scientific and technological cooperation of Dalian [2015F11GH095]
- Cancer Research UK Imperial Centre
- Imperial ECMC
- NIHR Imperial BRC
- MRC [MR/N012097/1] Funding Source: UKRI
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Estrogen receptor beta (ER beta) plays critical roles in thyroid cancer progression. However, its role in thyroid cancer stem cell maintenance remains elusive. Here, we report that ER beta is overexpressed in papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ER beta decreases stemness-related factors expression, diminishes ALDH(+) cell populations, and suppresses sphere formation ability and tumor growth. Screening estrogen-responsive lncRNAs in PTC spheroid cells, we find that lncRNA-H19 is highly expressed in PTCSCs and PTC tissue specimens, which is correlated with poor overall survival. Mechanistically, estradiol (E2) significantly promotes H19 transcription via ER beta and elevates H19 expression. Silencing of H19 inhibits E2-induced sphere formation ability. Furthermore, H19 acting as a competitive endogenous RNA sequesters miRNA-3126-5p to reciprocally release ER beta expression. ER beta depletion reverses H19-induced stem-like properties upon E2 treatment. Appropriately, ER beta is upregulated in PTC tissue specimens. Notably, aspirin attenuates E2-induced cancer stem-like traits through decreasing both H19 and ER beta expression. Collectively, our findings reveal that ER beta-H19 positive feedback loop has a compelling role in PTCSC maintenance under E2 treatment and provides a potential therapeutic targeting strategy for PTC.
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