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Oncogene ; 42(18): 1419-1437, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36922677

RESUMEN

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 CD24loCD44hi 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.


Asunto(s)
Neoplasias de la Mama , ARN Largo no Codificante , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Interleucina-6/metabolismo , Transducción de Señal , Fenotipo , Neoplasias de la Mama Triple Negativas/patología , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa/metabolismo , Células Madre Neoplásicas/patología , Línea Celular Tumoral , Neoplasias de la Mama/patología , Factor de Transcripción STAT3/metabolismo
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