4.8 Article

LncRNA Uc003xsl.1-Mediated Activation of the NFKB/IL8 Axis Promotes Progression of Triple-Negative Breast Cancer

期刊

CANCER RESEARCH
卷 82, 期 4, 页码 556-570

出版社

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-1446

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资金

  1. National Science and Technology Major Project [2020ZX09201021]
  2. National Natural Science Foundation of China [81972471, 81730077, 82025026]
  3. Guangdong Basic and Applied Basic Research Foundation [2020A1515010115, 2019A1515110082]
  4. Guangdong province Science and Technology Plan Foundation [A2019259]
  5. Guangzhou Science and Technology Major Program [201704020131]
  6. Guangdong Science and Technology Department [2017B030314026]
  7. Sun Yat-sen University Clinical Research 5010 Program [2018007]
  8. Sun Yat-sen Clinical Research Cultivating Program [SYS-C-201801]
  9. Medical Artificial Intelligence Project of Sun Yat-sen Memorial Hospital [YXRGZN201902]
  10. China Postdoctoral Science Foundation [2020TQ0377]

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This study identifies an epigenetic-driven NF kappa B/IL8 cascade initiated by a lncRNA, whose aberrant activation contributes to tumor metastasis and poor survival in patients with triple-negative breast cancer.
Aberrant activation of NF kappa B orchestrates a critical role in tumor carcinogenesis; however, the regulatory mechanisms underlying this activation are not fully understood. Here we report that a novel long noncoding RNA (lncRNA) Uc003xsl.1 is highly expressed in triple-negative breast cancer (TNBC) and correlates with poor outcomes in patients with TNBC. Uc003xsl.1 directly bound nuclear transcriptional factor NF kappa B-repressing factor (NKRF), subsequently preventing NKRF from binding to a specific negative regulatory element in the promoter of the NF kappa B-responsive gene IL8 and abolishing the negative regulation of NKRF on NF kappa B-mediated transcription of IL8. Activation of the NF kappa B/IL8 axis promoted the progression of TNBC. Trop2-based antibody-drug conjugates have been applied in clinical trials in TNBC. In this study, a Trop2-targeting, redox-responsive nano-particle was developed to systematically deliver Uc003xsl.1 siRNA to TNBC cells in vivo, which reduced Uc003xsl.1 expression and suppressed TNBC tumor growth and metastasis. Therefore, target-ing Uc003xsl.1 to suppress the NF kappa B/IL8 axis represents a prom-ising therapeutic strategy for TNBC treatment. Significance: These findings identify an epigenetic-driven NF kappa B/IL8 cascade initiated by a lncRNA, whose aberrant acti-vation contributes to tumor metastasis and poor survival in patients with triple-negative breast cancer.

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