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m6A reader IGF2BP2 promotes lymphatic metastasis by stabilizing DPP4 in papillary thyroid carcinoma

Cancer Gene Therapy volume 31, pages 285–299 (2024)Cite this article

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Abstract

Lymph node metastasis (LNM) is a major cause of locoregional recurrence of papillary thyroid carcinoma (PTC). However, the mechanisms responsible for LNM are unclear. Aberrant N6-methyladenosine (m6A) RNA modification plays a vital role in cancer progression and metastasis, and whether m6A modification regulates LNM in PTC remains to be determined. This study showed that IGF2BP2 was upregulated in PTC and positively associated with LNM. Functionally, IGF2BP2 knockdown significantly inhibited PTC cell proliferation and invasion in vitro, and vice versa. Moreover, IGF2BP2 knockdown significantly inhibited lymphatic metastasis in vivo. Mechanistically, Human m6A epitranscriptomic microarray, MeRIP, and RIP assays demonstrated that IGF2BP2 activated the NF-KB pathway by enhancing DPP4 stability in an m6A-dependent manner. Furthermore, IGF2BP2 knockdown increased the sensitivity of PTC cells to cisplatin therapy to a certain extent, while its overexpression produced the opposite effects. Overall, this study uncovers that IGF2BP2 promotes lymphatic metastasis via stabilizing DPP4 in an m6A-dependent manner, and provides new insights for understanding the mechanism of lymphatic metastasis in PTC.

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Fig. 1: A nomogram was constructed for predicting the LNM of PTC.
Fig. 2: IGF2BP2 was a potential predictive marker for LNM in PTC.
Fig. 3: Knockdown of IGF2BP2 inhibited the proliferation, migration, and invasion of PTC cells in vitro.
Fig. 4: Overexpression of IGF2BP2 promoted the proliferation, migration, and invasion of PTC cells in vitro.
Fig. 5: IGF2BP2 knockdown suppressed the lymphatic metastasis in vivo.
Fig. 6: IGF2BP2 enhanced the stability of DPP4 mRNA via m6A modification.
Fig. 7: IGF2BP2/DPP4 axis regulated the proliferation and invasion of PTC cells.
Fig. 8: IGF2BP2/DPP4 axis modulated the NF-KB signaling pathway in PTC cells.
Fig. 9: IGF2BP2 knockdown enhanced the chemosensitivity of PTC cells.
Fig. 10: A graphic illustration of the proposed mechanism in this study.

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Data availability

All data analyzed in this study are available from the corresponding author upon reasonable request.

Code availability

All codes analyzed in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We sincerely thank all team members for their assistance in this work.

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Author notes

  1. These authors contributed equally: Wenlong Wang, Ying Ding.

Authors and Affiliations

  1. Department of General Surgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China

    Wenlong Wang, Yunzhe Zhao & Xinying Li

  2. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, Hunan Province, China

    Wenlong Wang & Xinying Li

  3. Department of Breast Thyroid Surgery, Third Xiangya Hospital, Central South University, 410013, Changsha, Hunan, China

    Ying Ding

  4. Postdoctoral Station of Medical Aspects of Specific Environments, the Third Xiangya Hospital, Central South University, Changsha, China

    Ying Ding

  5. Department of Oncology, Third Xiangya Hospital, Central South University, 410013, Changsha, Hunan, China

    Ying Ding

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Contributions

WLW and XYL conceived and designed this study. WLW, YZZ, and YD performed the study and wrote the paper. YD and YYZ participated in data analysis. WLW and YYZ collected the tissues. All authors read and approved the final manuscript.

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Correspondence to Yunzhe Zhao or Xinying Li.

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The research was approved by the Ethics Committee of the Xiangya Hospital of Central South University. All animal studies were conducted in accordance with the principles and procedures outlined in the guidelines of the Institutional Animal Care and Use Committee (IACUC) of Central South University.

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Wang, W., Ding, Y., Zhao, Y. et al. m6A reader IGF2BP2 promotes lymphatic metastasis by stabilizing DPP4 in papillary thyroid carcinoma. Cancer Gene Ther 31, 285–299 (2024). https://doi.org/10.1038/s41417-023-00702-2

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