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TRIM32 promotes radioresistance by disrupting TC45-STAT3 interaction in triple-negative breast cancer

Oncogene volume 41, pages 1589–1599 (2022)Cite this article

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Abstract

Radioresistance is common in the treatment of triple-negative breast cancer (TNBC), but the molecular mechanisms involved remain unclear. Herein, we reveal that tripartite motif-containing protein 32 (TRIM32) is upregulated in TNBC and is negatively associated with survival of TNBC patients. Radiotherapy resulted in enhanced expression of TRIM32, whereas TRIM32 depletion reduced TNBC radioresistance in vitro and in vivo. Mechanistically, radiotherapy promoted the association between TRIM32 and nuclear STAT3, which suppressed TC45-induced dephosphorylation of STAT3, resulting in increased STAT3 transcriptional activation and TNBC radioresistance. Finally, we demonstrated that TRIM32 and STAT3 phosphorylation are co-expressed in TNBC tissues. Moreover, high expression of TRIM32 and STAT3 phosphorylation is positively linked to poor prognosis of TNBC patients. Our study demonstrates that TRIM32 is a novel target for predicting radioresistance in TNBC patients.

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Fig. 1: TRIM32 is upregulated in TNBC and is negatively associated with prognosis of TNBC patients.
Fig. 2: TRIM32 is transcriptionally upregulated by radiotherapy.
Fig. 3: TRIM32 enhances radioresistance in TNBC cells.
Fig. 4: TRIM32 promotes TNBC radioresistance by enhancing STAT3 phosphorylation.
Fig. 5: Radiotherapy promotes TRIM32 interaction with STAT3 in the nucleus.
Fig. 6: Y528/Q531 sites of TRIM32 are important for TNBC radioresistance.
Fig. 7: TRIM32 induces STAT3 phosphorylation by disrupting STAT3-TC45 interaction.
Fig. 8: Co-expression of TRIM32 and p-STAT3Y705 in clinical TNBC samples.

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Funding

This study was supported, in part, by grants from the National Natural Science Foundation of China (Grant number: 82003236 to Haibo Zhang), Zhejiang Provincial Nature Science Foundation of China (Grant number: LQ20H160063 to Jianming Tang), Gansu Provincial National Science Foundation for Distinguished Young Scholars (Grant number: 21JR7RA389 to Jianming Tang), Zhejiang Provincial Nature Science Foundation of China (Grant number: LY20H160044 to Ying Wang).

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Author notes

  1. These authors contributed equally: Yan Ma, Haibo Zhang, Cheng Chen, Lixin Liu, Ting Ding.

Authors and Affiliations

  1. Department of Radiation Oncology, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu, 730000, P.R. China

    Yan Ma, Xiaohua Chen & Jianming Tang

  2. Oncology center, Department of Radiation Oncology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, P.R. China

    Haibo Zhang & Ying Wang

  3. Department of Breast Surgery, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu, 730000, P.R. China

    Cheng Chen & Dachang Ma

  4. Department of thoracic surgery, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu, 730000, P.R. China

    Lixin Liu

  5. Department of endocrinology, Yiyang Central Hospital, Yiyang, Hunan, 413000, P.R. China

    Ting Ding

  6. Department of Oncology, The First Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu, 730000, P.R. China

    Xiaoling Ling

  7. Shanghai Bioegene Co.,Ltd, Shanghai, 200003, P.R. China

    Jianping Li

  8. Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China

    Zhong

  9. Department of Pathology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Zhejiang, 310014, P.R. China

    Guoqing Ru

  10. Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China

    Lei Zhang

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  1. Yan Ma
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Contributions

LZ, JT, YM, and HZ conceived and designed experiments. YM, HZ, CC, LL, TD, YW, DM, XL, XC, JL, GZ, and GR performed the experiments. JT developed the imaging analysis. JT and HZ wrote the paper.

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Correspondence to Lei Zhang or Jianming Tang.

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Ma, Y., Zhang, H., Chen, C. et al. TRIM32 promotes radioresistance by disrupting TC45-STAT3 interaction in triple-negative breast cancer. Oncogene 41, 1589–1599 (2022). https://doi.org/10.1038/s41388-022-02204-1

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