NKX2-1 re-expression induces cell death through apoptosis and necrosis in dedifferentiated thyroid carcinoma cells

Yuko Ito; Fumihiko Furuya; Katsumi Taki; Hideaki Suzuki; Hiroki Shimura

doi:10.1371/journal.pone.0259558

NKX2-1 re-expression induces cell death through apoptosis and necrosis in dedifferentiated thyroid carcinoma cells

PLoS One. 2021 Nov 8;16(11):e0259558. doi: 10.1371/journal.pone.0259558. eCollection 2021.

Authors

Yuko Ito¹, Fumihiko Furuya², Katsumi Taki³, Hideaki Suzuki^{1

4}, Hiroki Shimura¹

Affiliations

¹ Department of Laboratory Medicine, School of Medicine, Fukushima Medical University, Fukushima, Fukushima, Japan.
² Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan.
³ Department of Internal Medicine, Fujiyoshida Municipal Medical Center, Fujiyoshida, Yamanashi, Japan.
⁴ Department of Clinical Laboratory Sciences, School of Health Sciences, Fukushima Medical University, Fukushima, Fukushima, Japan.

Abstract

NK2 homeobox 1 (NKX2-1) is a thyroid transcription factor essential for proper thyroid formation and maintaining its physiological function. In thyroid cancer, NKX2-1 expression decreases in parallel with declined differentiation. However, the molecular pathways and mechanisms connecting NKX2-1 to thyroid cancer phenotypes are largely unknown. This study aimed to examine the effects of NKX2-1 re-expression on dedifferentiated thyroid cancer cell death and explore the underlying mechanisms. A human papillary thyroid carcinoma cell line lacking NKX2-1 expression was infected with an adenoviral vector containing Nkx2-1. Cell viability decreased after Nkx2-1 transduction and apoptosis and necrosis were detected. Arginase 2 (ARG2), regulator of G protein signaling 4 (RGS4), and RGS5 mRNA expression was greatly increased in Nkx2-1-transducted cells. After suppressing these genes by siRNA, cell death, apoptosis, and necrosis decreased in RGS4 knockdown cells. These findings demonstrated that cell death was induced via apoptosis and necrosis by NKX2-1 re-expression and involves RGS4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
Genes, Homeobox*
Humans
Necrosis*
Thyroid Nuclear Factor 1

Substances

NKX2-1 protein, human
Thyroid Nuclear Factor 1

Grants and funding

This work was supported by JSPS KAKENHI Grant Number JP16K08971 and JP17K15779, and by research grant from Roche Diagnostics K.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. JSPS website: https://www.jsps.go.jp. Roche Diagnostics K.K. website: https://www.roche-diagnostics.jp.