Cody Rutherford

Background: Thyroid cancer is the most common cancer of the endocrine system.¹ It accounts for about 90% of endocrine malignancies and 70% of endocrine cancer deaths.¹ It is the fifth most common cancer in the United States and the eighth most common cancer worldwide.^1,2 Papillary thyroid cancer (PTC) is a malignancy of the thyroid follicular cells and is the most common form of thyroid cancer.^2,3 PTC has varying aggressiveness and is associated with lymph node metastasis in 40% of cases.⁴ Early lymph node metastasis is a poor prognostic factor and is associated with lower survival rates and higher recurrence rates.⁴ In advanced stages of PTC, treatments such as immune checkpoint inhibitors become important, but their effectiveness varies greatly.⁵  Methyltransferase-like-3 (METTL3) is an N6-methyladenosine (m6A) writer capable of post-transcriptional modification of eukaryotic mRNA. Research has found METTL3 exhibits both oncogenic and tumor-suppressive effects, depending on the type of cancer it is present in. Current research shows that METTL3 is downregulated in PTC tissues compared to healthy tissues, which is associated with poor prognosis.^5,6 METTL3 affects other cancers through multiple mechanisms such as regulating gene expression and affecting the tumor microenvironment, but its actions in PTC are unclear.⁶

Objective: This narrative review will explore mechanisms related to the role of METTL3-mediated m6A modification in tumorigenesis and treatment of dangerous phenotypes of papillary thyroid cancer.

Search Methods: An online search of the PubMed database was conducted for articles published from 2019-2024 using the search string: “papillary thyroid cancer” AND “METTL3”.

Results: Current research shows that METTL3 expression is downregulated in PTC tissues compared to healthy thyroid tissues.^5,6 This downregulation is associated with tumor progression, poor prognosis, immune suppression, and resistance to immune checkpoint inhibitors.^5,6 Loss-of-function studies using short-hairpin RNA of METTL3 found that low METTL3 expression increases migration and invasion cell numbers in vitro.⁷ In vivo, these loss-of-function studies increased the number of metastatic nodules in the lungs of mice models.⁷ Database analysis shows METTL3 stabilizes six-transmembrane epithelial antigen of prostate 2 (STEAP2) and increases its translation.⁷ Overexpression of METTL3 increases levels of STEAP2 and decreases epithelial-to-mesenchymal transition (EMT) of thyroid cancer cell lines.⁷ This prevents them from gaining mesenchymal cell characteristics of motility and invasiveness.⁷ The therapeutic effect of overexpressing METTL3 is reversed when STEAP2 expression is silenced.⁷  Overexpression of METTL3 also enhances the efficacy of the immune checkpoint inhibitor, anti-PD-1.⁵ METTL3 overexpression in combination with anti-PD-1 greatly lowers tumor burden and metastatic nodules, and increases CD8⁺ T-cells.⁵

Conclusion: Papillary thyroid cancer is a highly prevalent endocrine malignancy associated with early lymph node metastasis.⁴ METTL3 expression is downregulated in PTC tissues which drives tumor progression and lymphatic metastasis.^5,6 Increasing expression of METTL3 restrains aggressive phenotypes by stabilizing STEAP2 and blocking epithelial-to-mesenchymal transition.⁷ In aggressive PTC, METTL3 enhances anti-cancer therapy.⁵ The creation of METTL3 activators, alone and in combination with immune checkpoint inhibitors, and STEAP2 as a therapeutic target should be considered as novel treatments of PTC.

Work Cited:

1. Varricchi G, Loffredo S, Marone G et al. The immune landscape of thyroid cancer in the context of immune checkpoint inhibition. Int J Mol Sci. 2019;20(16):3934. doi:10.3390/ijms20163934.
2. Fallahi P, Ferrari SM, Galdiero MR et al. Molecular targets of tyrosine kinase inhibitors in thyroid cancer. Semin Cancer Biol. 2022;79:180-196. doi:10.1016/j.semcancer.2020.11.013.
3. Boucai L, Zafereo M, Cabanillas ME. Thyroid cancer: a review. 2024;331(5):425-435. doi:10.1001/jama.2023.26348.
4. Zhou X, Chang L, Liang Q et al. The m6a methyltransferase METTL3 drives thyroid cancer progression and lymph node metastasis by targeting LINC00894. Cancer Cell Int. 2024;24(1):47. doi:10.1186/s12935-024-03240-5.
5. Ning J, Hou X, Hao J et al. METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer. Cell Death Differ. 2023;30(10):2265-2279. doi:10.1038/s41418-023-01217-x.
6. He J, Zhou M, Yin J et al. METTL3 restrains papillary thyroid cancer progression via m⁶A/c-Rel/IL-8-mediated neutrophil infiltration. Mol Ther. 2021;29(5):1821-1837. doi:10.1016/j.ymthe.2021.01.019.
7. Zhu Y, Peng X, Zhou Q et al. METTL3-mediated m6A modification of STEAP2 mRNA inhibits papillary thyroid cancer progress by blocking the Hedgehog signaling pathway and epithelial-to-mesenchymal transition. Cell Death Dis. 2022;13(4):358. doi:10.1038/s41419-022-04817-6.