A micropeptide XBP1SBM encoded by lncRNA promotes angiogenesis and metastasis of TNBC via XBP1s pathway

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with a poor prognosis. To date, the mechanism of TNBC's aggressive phenotype is still unclear. Based on metabolome analysis, we found that glutamine (Gln) metabolism plays a key role in the difference between TN...

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Bibliographic Details
Published in:Oncogene 2022-04, Vol.41 (15), p.2163-2172
Main Authors: Wu, Siqi, Guo, Binbin, Zhang, Liyuan, Zhu, Xun, Zhao, Peipei, Deng, Jieqiong, Zheng, Jian, Li, Fang, Wang, Yirong, Zhang, Shenghua, Zhang, Zheng, Lu, Jiachun, Zhou, Yifeng
Format: Article
Language:English
Subjects:
Angiogenesis
Animal models
Animals
Breast cancer
Cell culture
Cell Line, Tumor
Endothelial cells
Endothelial Cells - metabolism
Gene Expression Regulation, Neoplastic
Glutamine
Humans
Medical prognosis
Metastases
Metastasis
Mice
Neovascularization, Pathologic - genetics
Non-coding RNA
Nutrient deficiency
Phenotypes
RNA, Long Noncoding - genetics
RNA, Long Noncoding - metabolism
Therapeutic targets
Transcription
Triple Negative Breast Neoplasms - pathology
Vascular endothelial growth factor
X-Box Binding Protein 1 - genetics
X-Box Binding Protein 1 - metabolism
Xenografts
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Summary:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with a poor prognosis. To date, the mechanism of TNBC's aggressive phenotype is still unclear. Based on metabolome analysis, we found that glutamine (Gln) metabolism plays a key role in the difference between TNBC and non-TNBC. We identified a 21-amino-acid survival-associated micropeptide XBP1SBM, encoded by the lncRNA MLLT4-AS1, which was upregulated in TNBC tissues and Gln-deprived TNBC cell lines. We showed that XBP1SBM expression was upregulated by Gln-deprivation-induced XBP1s transcriptional promotion, and in turn retained XBP1s in the nuclear to enhance the expression of VEGF. Using human endothelial cells, mouse xenograft models and mouse spontaneous BC models, we found that XBP1SBM improved Gln levels and promoted angiogenesis and metastasis in TNBC. Our study showed that a TNBC-specific nutrient deficiency adaption results in aggressive TNBC, and this mechanism provides a novel potential prognostic biomarker and therapeutic target in TNBC.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-022-02229-6