Phenytoin Inhibits Cell Proliferation through microRNA-196a-5p in Mouse Lip Mesenchymal Cells

Authors

Hiroki Yoshioka
Sai Shankar Ramakrishnan
Akiko Suzuki
Junichi Iwata

Publication Date

2-9-2021

Journal

International Journal of Molecular Sciences

Abstract

Cleft lip (CL) is one of the most common birth defects. It is caused by either genetic mutations or environmental factors. Recent studies suggest that environmental factors influence the expression of noncoding RNAs [e.g., microRNA (miRNA)], which can regulate the expression of genes crucial for cellular functions. In this study, we examined which miRNAs are associated with CL. Among 10 candidate miRNAs (miR-98-3p, miR-101a-3p, miR-101b-3p, miR-141-3p, miR-144-3p, miR-181a-5p, miR-196a-5p, miR-196b-5p, miR-200a-3p, and miR-710) identified through our bioinformatic analysis of CL-associated genes, overexpression of miR-181a-5p, miR-196a-5p, miR-196b-5p, and miR-710 inhibited cell proliferation through suppression of genes associated with CL in cultured mouse embryonic lip mesenchymal cells (MELM cells) and O9-1 cells, a mouse cranial neural crest cell line. In addition, we found that phenytoin, an inducer of CL, decreased cell proliferation through miR-196a-5p induction. Notably, treatment with a specific inhibitor for miR-196a-5p restored cell proliferation through normalization of expression of CL-associated genes in the cells treated with phenytoin. Taken together, our results suggest that phenytoin induces CL through miR-196a-5p induction, which suppresses the expression of CL-associated genes.

Keywords

Animals, Cell Line, Cell Proliferation, Cleft Lip, Disease Models, Animal, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Humans, Lip, Maternal Exposure, Mesenchymal Stem Cells, Mice, MicroRNAs, Mouse Embryonic Stem Cells, Phenytoin, Primary Cell Culture, Teratogens

DOI

10.3390/ijms22041746

PMID

33572377

PMCID

PMC7916186

PubMedCentral® Posted Date

2-9-2021

PubMedCentral® Full Text Version

Post-print

Recommended Citation

Yoshioka, Hiroki; Ramakrishnan, Sai Shankar; Suzuki, Akiko; and Iwata, Junichi, "Phenytoin Inhibits Cell Proliferation through microRNA-196a-5p in Mouse Lip Mesenchymal Cells" (2021). Faculty, Staff and Student Publications. 84.
https://digitalcommons.library.tmc.edu/uthdb_docs/84

Published Open-Access

yes