PMID- 36922677 OWN - NLM STAT- MEDLINE DCOM- 20230504 LR - 20230818 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 42 IP - 18 DP - 2023 May TI - LncRNA XIST regulates breast cancer stem cells by activating proinflammatory IL-6/STAT3 signaling. PG - 1419-1437 LID - 10.1038/s41388-023-02652-3 [doi] AB - 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. CI - (c) 2023. The Author(s). FAU - Ma, Yuxi AU - Ma Y AD - Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. AD - Department of Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. FAU - Zhu, Yongyou AU - Zhu Y AD - Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. FAU - Shang, Li AU - Shang L AD - Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. AD - University of Michigan Rogel Cancer Center, Ann Arbor, MI, 48109, USA. FAU - Qiu, Yan AU - Qiu Y AD - Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. FAU - Shen, Na AU - Shen N AD - Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. AD - Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. FAU - Wang, Jonathan AU - Wang J AD - Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. FAU - Adam, Tiffany AU - Adam T AD - Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. FAU - Wei, Wei AU - Wei W AD - Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China. FAU - Song, Qingxuan AU - Song Q AD - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. FAU - Li, Jun AU - Li J AD - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. FAU - Wicha, Max S AU - Wicha MS AUID- ORCID: 0000-0003-4180-7727 AD - Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. mwicha@med.umich.edu. AD - University of Michigan Rogel Cancer Center, Ann Arbor, MI, 48109, USA. mwicha@med.umich.edu. FAU - Luo, Ming AU - Luo M AUID- ORCID: 0000-0002-0795-3678 AD - Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. mingluo@med.umich.edu. AD - University of Michigan Rogel Cancer Center, Ann Arbor, MI, 48109, USA. mingluo@med.umich.edu. AD - Department of Breast and Thyroid Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China. mingluo@med.umich.edu. LA - eng GR - P30 CA046592/CA/NCI NIH HHS/United States GR - R01 GM118928/GM/NIGMS NIH HHS/United States GR - R35 CA197585/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230315 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (RNA, Long Noncoding) RN - 0 (Interleukin-6) RN - EC 1.2.1.3 (Aldehyde Dehydrogenase) RN - 0 (STAT3 protein, human) RN - 0 (STAT3 Transcription Factor) SB - IM MH - Humans MH - Female MH - *RNA, Long Noncoding/genetics/metabolism MH - Interleukin-6/metabolism MH - Signal Transduction MH - Phenotype MH - *Triple Negative Breast Neoplasms/pathology MH - Aldehyde Dehydrogenase/genetics/metabolism MH - Neoplastic Stem Cells/pathology MH - Cell Line, Tumor MH - *Breast Neoplasms/pathology MH - STAT3 Transcription Factor/metabolism PMC - PMC10154203 COIS- The authors declare no competing interests. EDAT- 2023/03/17 06:00 MHDA- 2023/05/04 12:41 PMCR- 2023/03/15 CRDT- 2023/03/16 01:04 PHST- 2022/09/20 00:00 [received] PHST- 2023/02/24 00:00 [accepted] PHST- 2023/02/19 00:00 [revised] PHST- 2023/05/04 12:41 [medline] PHST- 2023/03/17 06:00 [pubmed] PHST- 2023/03/16 01:04 [entrez] PHST- 2023/03/15 00:00 [pmc-release] AID - 10.1038/s41388-023-02652-3 [pii] AID - 2652 [pii] AID - 10.1038/s41388-023-02652-3 [doi] PST - ppublish SO - Oncogene. 2023 May;42(18):1419-1437. doi: 10.1038/s41388-023-02652-3. Epub 2023 Mar 15.