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Abstract
Estrogen receptor β (ERβ) plays critical roles in thyroid cancer progression. However, its role in thyroid cancer stem cell maintenance remains elusive. Here, we report that ERβ is overexpressed in papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ERβ 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 ERβ 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 ERβ expression. ERβ depletion reverses H19-induced stem-like properties upon E2 treatment. Appropriately, ERβ is upregulated in PTC tissue specimens. Notably, aspirin attenuates E2-induced cancer stem-like traits through decreasing both H19 and ERβ expression. Collectively, our findings reveal that ERβ-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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1 The First Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China; Dongfang Hospital, Key Laboratory of Health Cultivation of the Ministry of Education, Beijing University of Chinese Medicine, Beijing, China
2 The First Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
3 The First Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China
4 Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
5 Dalian Municipal Women And Children’s Medical Center, Dalian, China
6 Departmemt of Pathology, Dalian Medical University, Dalian, China
7 Department of Surgery and Cancer, Imperial College London, London, UK