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

Oncogene volume 41, pages 2163–2172 (2022)Cite this article

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Abstract

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.

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Fig. 1: Identification of TNBC-specific and Gln-deprived-associated lncRNA with coding ability.
Fig. 2: XBP1SBM associated with TNBC tumor growth and overall survival of TNBC patients.
Fig. 3: XBP1s regulate MLLT4-AS1 transcription.
Fig. 4: XBP1SBM interact with XBP1s.
Fig. 5: XBP1SBM inhibits the interaction between XBP1s and XBP1u and regulates the subcellular localization of XBP1s.
Fig. 6: XBP1SBM promote TNBC angiogenesis and metastasis.
Fig. 7: XBP1SBM promotes TNBC angiogenesis and metastasis by regulating XBP1s pathway.

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Acknowledgements

This work was supported by The National Scientific Foundation of China grants 82103263, 81772544 and 81972649; The National Science Fund for Distinguished Young Scholars 82125027; Program for Guangdong Introducing Innovative and Entrepreneurial Teams (2017ZT07S096).

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Author notes

  1. These authors contributed equally: Siqi Wu, Binbin Guo, Liyuan Zhang, Xun Zhu.

Authors and Affiliations

  1. Department of Genetics, Medical College of Soochow University, Suzhou, 215123, China

    Siqi Wu, Binbin Guo, Jieqiong Deng, Fang Li, Yirong Wang, Shenghua Zhang, Zheng Zhang & Yifeng Zhou

  2. Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, China

    Liyuan Zhang & Peipei Zhao

  3. Department of General Surgery, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou, 215004, China

    Xun Zhu

  4. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China

    Jian Zheng & Yifeng Zhou

  5. The Institute for Chemical Carcinogenesis, The First Affiliated Hospital, The School of Public Health, Guangzhou Medical University, Guangzhou, 510182, China

    Jiachun Lu

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Contributions

SW and YZ designed the experiments, analyzed the data and revised the manuscript. SW wrote the manuscript. SW, LZ, and XZ performed most of the experiments. YW, BG, and FL performed the experiments. All of the authors discussed the results and reviewed the manuscript.

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Correspondence to Yifeng Zhou.

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Wu, S., Guo, B., Zhang, L. et al. A micropeptide XBP1SBM encoded by lncRNA promotes angiogenesis and metastasis of TNBC via XBP1s pathway. Oncogene 41, 2163–2172 (2022). https://doi.org/10.1038/s41388-022-02229-6

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