METTL3-Induced miR-222-3p Upregulation Inhibits STK4 and Promotes the Malignant Behaviors of Thyroid Carcinoma Cells.

Abstract

CONTEXT:

Abnormally high expression of N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) has been implied to accompany thyroid carcinoma (TC) development.

OBJECTIVE:

This study aimed to explore the protumorigenic role and downstream signaling axis of METTL3 in TC.

METHODS:

This study was conducted at the Sun Yat-Sen Memorial Hospital Sun Yat-Sen University. METTL3 and miR-222-3p were overexpressed or downregulated in TC cells. Tumor and adjacent normal tissues were collected from 80 patients (19 men and 60 women, aged 30-70 years) with a pathological diagnosis of TC from January 2012 to January 2015. Cells were classified and subjected to different treatments. The expression of METTL3 was validated in TC tissues and cell lines. In functional studies, METTL3 and miR-222-3p were overexpressed or downregulated in TC cells to evaluate their effects on malignant behaviors, which were subsequently verified by xenografts in nude mice.

RESULTS:

The expression of METTL3 was elevated in TC, correlating with poor prognosis of TC patients. Heightened METTL3 expression accelerated malignant behaviors of TC cells. Mechanistically, METTL3 stimulated miR-222-3p expression by mediating the m6A modification of pri-miR-222-3p. miR-222-3p targeted and inversely regulated serine/threonine stress kinase 4 (STK4). Knockdown of METTL3 augmented STK4 expression by downregulating miR-222-3p, thereby suppressing the malignant behaviors of TC cells as well as tumor growth and lung metastasis in nude mice.

CONCLUSION:

Silencing METTL3 suppresses miR-222-3p expression and thus stimulates STK4 expression, thereby repressing the malignancy and metastasis of TC.

• Authors: Shaojian Lin, Yue Zhu, Chengcheng Ji, Weiming Yu, Cheng Zhang, Langping Tan, Miaoyun Long, Dingyuan Luo, Xinzhi Peng
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 107 Issue 2 Pg. 474-490 (01 18 2022) ISSN: 1945-7197 [Electronic] United States
• PMID: 34562008 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Intracellular Signaling Peptides and Proteins
• MIRN222 microRNA, mouse
• MicroRNAs
• N-methyladenosine
• Methyltransferases
• METTL3 protein, human
• STK4 protein, human
• Protein Serine-Threonine Kinases
• Adenosine

Topics

• Adenosine (analogs & derivatives, metabolism)
• Adult
• Aged
• Animals
• Cell Transformation, Neoplastic (genetics)
• Down-Regulation
• Female
• Follow-Up Studies
• Gene Knockdown Techniques
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Kaplan-Meier Estimate
• Male
• Methyltransferases (genetics, metabolism)
• Mice
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Protein Serine-Threonine Kinases (genetics)
• Thyroid Gland (pathology, surgery)
• Thyroid Neoplasms (genetics, mortality, pathology, surgery)
• Thyroidectomy
• Up-Regulation
• Xenograft Model Antitumor Assays