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Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2

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Abstract

Background

Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) can be developed from differentiated thyroid cancer, and this dedifferentiated transformation leads to poor prognosis and high mortality. The role of Nrf2 in the dedifferentiation of differentiated thyroid cancer (DTC) induced by KRAS remains unclear.

Methods and materials

In this study, two DTC cell lines, BCPAP and WRO, were used to evaluate the function of Nrf2 in the dedifferentiation caused by wild-type KRAS (KRAS-WT) and G12V point mutation KRAS (KRAS-G12V).

Results

The overexpression of KRAS-WT and KRAS-G12V increased the proliferative and invasive ability of BCPAP and WRO cells. Aggressive morphology was observed in KRAS-WT and KRAS-G12V overexpressed WRO cells. These results suggested that overexpression of KRAS-WT or KRAS-G12V may induce dedifferentiation in DTC cells. The expression of Nrf2 was increased by KRAS-WT and KRAS-G12V in DTC cells. In addition, compared with normal thyroid tissues, the expression of Nrf2 protein was considerably higher in thyroid cancer tissues on immunohistochemistry (IHC) staining, and the increased expression of Nrf2 indicated a poor prognosis of thyroid cancer. These results indicated that Nrf2 is the KRAS downstream molecule in thyroid cancer. Functional studies showed that the Nrf2 inhibitor Brusatol counteracted the proliferative and invasive abilities induced by KRAS-WT and KRAS-G12V in BCPAP and WRO cells. In addition, the xenograft assay further confirmed that Brusatol inhibits tumor growth induced by KRAS-WT and KRAS-G12V.

Conclusion

Collectively, this study suggests that Nrf2 could be a promising therapeutic target in KRAS-mediated dedifferentiation of thyroid cancer.

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Data availability

Not applicable.

Abbreviations

ATC:

Anaplastic thyroid cancer

DTC:

Differentiated thyroid cancer

FTC:

Follicular thyroid cancer

IHC:

Immunohistochemistry

IRS:

Immunoreactive score

KRAS-G12V:

G12V point mutation KRAS

KRAS-WT:

Wild-type KRAS

PDTC:

Poorly differentiated thyroid cancer

PTC:

Papillary thyroid cancer

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Acknowledgements

We thank Dr. Jia Peng and Ms. SY Chun for their technical assistance.

Funding

This study was supported by grants from the National Natural Science Foundation of China (n. 81972493) and the Research Grants Council of the Hong Kong Special Administrative Region CUHK 14108921.

Author information

Authors and Affiliations

  1. Department of Otorhinolaryngology, Head and Neck Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China

    Z. Gong, L. Xue, A. C. Vlantis, C. A. van Hasselt, J. Y. K. Chan, M. C. F. Tong & G. G. Chen

  2. Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, Guangdong, China

    Z. Gong, M. C. F. Tong & G. G. Chen

  3. Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China

    J. Fang, R. Wang & Y. Yang

  4. Key Laboratory of Otolaryngology Head and Neck Surgery (Ministry of Education of China), Beijing Institute of Otolaryngology, Beijing, China

    J. Fang, R. Wang & Y. Yang

  5. Shenzhen Key Laboratory of ENT, Institute of ENT and Longgang ENT Hospital, Shenzhen, Guangdong, China

    D. Li & X. Zeng

Authors
  1. Z. Gong
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  2. L. Xue
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  12. G. G. Chen
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Contributions

Study design and concept: ZG, MT, GC. Data acquisition: ZG, LX, AV, CV, JC. Data analysis and interpretation: ZG, JF, RW. Collection of clinical data and sample disposal: ZG, YY, DL, XZ, Manuscript preparation: ZG, GC. Manuscript review: GC, MT. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to M. C. F. Tong or G. G. Chen.

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Conflict of interest

All authors declare that there is no conflict of interest.

Ethical approval and consent to participate

Human studies were approved by the Joint CUHK-NTEC Clinical Research Ethics Committee, which is accordance with the Declaration of Helsinki.

Animal ethic approval

All procedures of mouse experiments were approved by the Animal Ethics Committee of the Chinese University of Hong Kong.

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Gong, Z., Xue, L., Vlantis, A.C. et al. Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2. J Endocrinol Invest 47, 1271–1280 (2024). https://doi.org/10.1007/s40618-023-02248-4

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  • DOI: https://doi.org/10.1007/s40618-023-02248-4

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