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The lncRNA THOR interacts with and stabilizes hnRNPD to promote cell proliferation and metastasis in breast cancer

Oncogene volume 41, pages 5298–5314 (2022)Cite this article

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Abstract

Emerging evidence shows that the lncRNA THOR is deeply involved in the development of various cancers. However, the effects and underlying molecular mechanisms of THOR in breast cancer (BRCA) initiation and progression have not been fully elucidated. Here we show that THOR is critical for BRCA tumorigenesis by interacting with hnRNPD to regulate downstream signaling pathways. THOR expression was significantly higher in BRCA tissues than in normal tissues, and THOR upregulation was associated with a poor prognosis in BRCA patients. Functionally, THOR knockdown impaired cell proliferation, migration and invasion in BRCA cells in vitro and inhibited tumorigenesis and metastasis in a tumor xenograft model and THOR-deficient MMTV-PyMT model in vivo. Mechanistically, THOR bound to the hnRNPD protein and increased hnRNPD protein levels by maintaining hnRNPD protein stability through inhibition of the proteasome-dependent degradation pathway. The increased hnRNPD protein levels led to stabilization of its target mRNAs, including pyruvate dehydrogenase kinase 1 (PDK1), further activating downstream PI3K–AKT and MAPK signaling pathways to regulate BRCA cell proliferation and metastasis. Together, our findings indicate that THOR is a promising prognostic predictor for BRCA patients and that the THOR–hnRNPD–PDK1–MAPK/PI3K–AKT axis might be a potential therapeutic target for BRCA treatment.

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Fig. 1: THOR is upregulated and correlates with a poor prognosis in breast cancer.
Fig. 2: THOR promotes breast cancer cell proliferation and metastasis in vitro.
Fig. 3: THOR interacts with hnRNPD and stabilizes hnRNPD protein.
Fig. 4: THOR regulates the MAPK/AKT signaling pathway through hnRNPD.
Fig. 5: THOR stabilizes hnRNPD protein to promote breast cancer progression.
Fig. 6: THOR promotes BRCA cell proliferation and metastasis via MAPK/AKT signaling pathways.
Fig. 7: Knockout of THOR inhibits breast cancer cell proliferation and metastasis in vivo.
Fig. 8: Clinical relevance of the THOR–hnRNPD complex in breast cancer.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank Xiaoguo Zheng and Chuanjin Yu at the International Peace Maternity and Child Health Hospital for their efforts in constructing THOR-KO cells by CRISPR–Cas9 technology. We thank Xin Ye at the International Peace Maternity and Child Health Hospital for helping collect clinical specimens. We also thank Rogier Versteeg and the Department of Oncogenomics at the Academic Medical Center (Amsterdam, The Netherlands) for providing the R2 Platform.

Funding

This work was supported by the National Natural Science Foundation of China (82088102, 82171686), National Key Research and Development Program of China (2021YFC2700701), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01), CAMS Innovation Fund for Medical Sciences (2019-I2M-5-064), Clinical Research Plan of SHDC (SHDC2020CR1008A), Shanghai Municipal Key Clinical Specialty (shslczdzk06302), Program of Shanghai Academic Research Leader (20XD1424100), Outstanding Youth Medical Talents of Shanghai Rising Stars of Medical Talent Youth Development Program, and Interdisciplinary Program of Shanghai Jiao Tong University (ZH2018QNB15, YG2019GD04, YG2020YQ29), Youth Talents development Program of Jiangsu Women And Children Health Hospital (FYRC202004), and Young Scholars Fostering Fund of the First Affiliated Hospital of Nanjing Medical University (PY2021009). The funding agencies had no role in the study design, data collection and analysis, or decision to submit the article for publication.

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Author notes

  1. These authors contributed equally: Hongtao Hu, Hanqiu Zhang.

Authors and Affiliations

  1. Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Hongtao Hu

  2. International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Hongtao Hu, Hanqiu Zhang, Jingjing Xu, Yanyan Guo, Jie Wang & Qi He

  3. Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China

    Hongtao Hu, Hanqiu Zhang, Cheng Li, Jingjing Xu, Xinmei Liu & Hefeng Huang

  4. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Yue Xing, Yan Zhou, Jianing Chen & Erwei Song

  5. Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Yue Xing, Yan Zhou, Jianing Chen & Erwei Song

  6. Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China

    Cheng Li, Xinmei Liu, Yanting Wu & Hefeng Huang

  7. Research Units of Embryo Original Diseases, Chinese Academy of Medical Sciences, Shanghai, China

    Xinmei Liu & Hefeng Huang

  8. Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou, China

    Jianzhong Sheng

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Contributions

The study was conceived and designed by HFH, EWS, YTW, and XML. HTH and HQZ collected clinical specimens and data, conducted most of the experiments and analyzed the data. JW and QH collected clinical specimens. YX, YZ, CL, JJX and YYG performed some of the experiments. HTH wrote the manuscript. JJX, JW and QH provided crucial reagents and took part in discussions. HFH, YTW, JZS, and JNC revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yanting Wu or Hefeng Huang.

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The authors declare no competing interests.

Ethics approval and consent to participate

Ethics approval for this study was granted by the Ethics Committee of the International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University and Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University. All patients provided written informed consent before participating in this study. All animal experiments were approved by the Institutional Animal Care and Use Committee of GemPharmatech Co., Ltd. (Nanjing, China).

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Hu, H., Zhang, H., Xing, Y. et al. The lncRNA THOR interacts with and stabilizes hnRNPD to promote cell proliferation and metastasis in breast cancer. Oncogene 41, 5298–5314 (2022). https://doi.org/10.1038/s41388-022-02495-4

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