Loss of NKX2-1 predisposes thyroid to neoplasm development through regulation of oxidative stress
Loss of NKX2-1 in thyroid cells may increase the risk of cancer by promoting oxidative stress, particularly in the presence of radiation and iodine deficiency.
Where it sits
this study against the rest of the glutathione (gsh) corpusSummary and findings
This study investigates the role of NKX2-1 in thyroid neoplasm development, using Nkx2-1 conditional knockout mice. The findings indicate that these mice develop thyroid adenoma and carcinoma more frequently when exposed to radiation and iodine deficiency. The study highlights the relationship between oxidative stress and thyroid carcinogenesis.
Abstract
Many factors including ionizing radiation and iodine deficiency are known to increase thyroid carcinogenesis risk. Our dataset analysis of The Cancer Genome Atlas (TCGA) showed that lower mRNA expression of NK2 homeobox 1 (NKX2-1) transcription factor, a master regulator of genesis, homeostasis, and function of thyroid, is linked to poor prognosis of papillary thyroid cancer patients. Here we provide the findings that thyroid-specific Nkx2-1 conditional knockout (Nkx2-1ΔT) mice develop thyroid adenoma and carcinoma in higher frequency with combined exposure to radiation and iodine deficiency than control Nkx2-1fl/fl mice. Iodine deficiency caused oxidative stress, which subsequently resulted in DNA damage, leading to transformation of thyroid follicular cells. RNA-seq gene set enrichment analysis indicated higher production of reactive oxygen species (ROS) in the thyroids of Nkx2-1ΔT as compared to Nkx2-1fl/fl mice with combined exposure to radiation and iodine deficiency. This was accompanied by a feedback induction of SOD3 (superoxide dismutase 3) and GPX2 (glutathione peroxidase 2). These antioxidants were naturally expressed at higher levels in the thyroids of Nkx2-1ΔT than Nkx2-1fl/fl mice without iodine deficiency or radiation. Nkx2-1ΔT thyroids exhibited abnormal follicle architecture and up-regulation of Acox2 (encoding acyl-CoA oxidase 2), which produces hydrogen peroxide. These results suggest that loss of NKX2-1 may contribute to excess ROS production, which elevates basal oxidative stress resulting in the promotion of ROS-induced carcinogenesis. We propose a role for NKX2-1 as a regulator of ROS production homeostasis in the thyroid. Its disturbance would dispose thyroid follicular cells more vulnerable to the ROS-producing carcinogens.
Background
The study appears to address the role of the NKX2-1 gene in thyroid neoplasm development, potentially through mechanisms involving oxidative stress. Glutathione (GSH) is a key antioxidant that may be relevant in this context. Understanding the genetic and oxidative stress factors in thyroid neoplasms could have implications for cancer research.
Methods
Not reported in abstract.
Results
Not reported in abstract.
Interpretation
Not reported in abstract.
Limitations
- Not reported in abstract.