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• W4324351612 abstract "Abstract Aberrant expression of XIST, a long noncoding RNA (lncRNA) initiating X chromosome inactivation (XCI) in early embryogenesis, is a common feature of breast cancer (BC). However, the roles of post-XCI XIST in breast carcinogenesis remain elusive. Here we identify XIST as a key regulator of breast cancer stem cells (CSCs), which exhibit aldehyde dehydrogenase positive (ALDH + ) epithelial- (E) and CD24 lo CD44 hi mesenchymal-like (M) phenotypes. XIST is variably expressed across the spectrum of BC subtypes, and doxycycline (DOX)-inducible knockdown (KD) of XIST markedly inhibits spheroid/colony forming capacity, tumor growth and tumor-initiating potential. This phenotype is attributed to impaired E-CSC in luminal and E- and M-CSC activities in triple-negative (TN) BC. Gene expression profiling unveils that XIST KD most significantly affects cytokine-cytokine receptor interactions, leading to markedly suppressed expression of proinflammatory cytokines IL-6 and IL-8 in ALDH - bulk BC cells. Exogenous IL-6, but not IL-8, rescues the reduced sphere-forming capacity and proportion of ALDH + E-CSCs in luminal and TN BC upon XIST KD. XIST functions as a nuclear sponge for microRNA let-7a-2-3p to activate IL-6 production from ALDH - bulk BC cells, which acts in a paracrine fashion on ALDH + E-CSCs that display elevated cell surface IL-6 receptor (IL6R) expression. This promotes CSC self-renewal via STAT3 activation and expression of key CSC factors including c-MYC, KLF4 and SOX9. Together, this study supports a novel role of XIST by derepressing let-7 controlled paracrine IL-6 proinflammatory signaling to promote CSC self-renewal." @default.
• W4324351612 created "2023-03-16" @default.
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• W4324351612 date "2023-03-15" @default.
• W4324351612 modified "2023-10-01" @default.
• W4324351612 title "LncRNA XIST regulates breast cancer stem cells by activating proinflammatory IL-6/STAT3 signaling" @default.
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• W4324351612 doi "https://doi.org/10.1038/s41388-023-02652-3" @default.
• W4324351612 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36922677" @default.
• W4324351612 hasPublicationYear "2023" @default.
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