Role of sodium/iodide symporter overexpression in inhibiting thyroid cancer cell invasion and stem cell maintenance by inhibiting the β-catenin/LEF-1 pathway

Nan-Fang Luo; Jia-Li Li; Juan Lv; Fu-Kun Chen; Ya-Nan Li; Ming Tang; Peng-Jie Liu

doi:10.1016/j.heliyon.2024.e27840

Role of sodium/iodide symporter overexpression in inhibiting thyroid cancer cell invasion and stem cell maintenance by inhibiting the β-catenin/LEF-1 pathway

Heliyon. 2024 Mar 14;10(6):e27840. doi: 10.1016/j.heliyon.2024.e27840. eCollection 2024 Mar 30.

Authors

Nan-Fang Luo¹, Jia-Li Li², Juan Lv², Fu-Kun Chen², Ya-Nan Li², Ming Tang³, Peng-Jie Liu²

Affiliations

¹ Department of Cardiac Function, The Cancer Hospital of Yunnan Province, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, China.
² Department of Nuclear Medicine, The Cancer Hospital of Yunnan Province, The Third Affiliated Hospital of Kunming Medical University, Kunming, 650118, China.
³ Department of Pathology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, China.

Abstract

Background: In thyroid cancers, a reduction in the expression of the sodium/iodide symporter (NIS) is observed concomitant with a diminution in cancer cell differentiation. The β-catenin/LEF-1 pathway emerges as a crucial regulatory pathway influencing the functional expression of NIS in human thyroid cancer cells. Further research is required to comprehensively elucidate the role of NIS overexpression in impeding the progression of thyroid cancer cells.

Methods: Human papillary thyroid carcinoma (PTC) cell lines, specifically PTC-1 and KTC-1, were subjected to Scratch and Transwell assays, colony formation, and tumor sphere formation tests to investigate invasion and migration, focusing on the impact of NIS overexpression. The assessment involved the use of western blot to analyze the expression levels of β-catenin, NIS, CD133, SRY-related HMG box2 (Sox2), lymphoid enhancer-binding factor 1 (LEF-1), NANOG, octamer-binding transcription factor 4 (Oct4), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), and epithelial cellular adhesion molecule (EpCAM). Statistical analysis was conducted using SPSS version 20.0, and the graphs were developed using GraphPad Prism 7 (GraphPad Software, Inc.).

Results: Our observations revealed that Nthy-ori-3-1 cell lines exhibited notably higher average expression levels of NIS, yet significantly lower levels of LEF-1 and β-catenin compared to PTC-1 and KTC-1 cell lines. Furthermore, the overexpression of β-catenin resulted in reduced binding of LEF-1 to NIF promotion but concurrently increased the expression of NIS. The downregulation of NIS markedly enhanced the expression of ALDH1A1, CD133, OCT4, Nanog, SOX2, and EpCam-all of which are targets within the Wnt/β-catenin signaling pathway. Conversely, the upregulation of NIS suppressed the expression of these proteins. Moreover, cells treated with β-catenin activators demonstrated an increased capability to form more spheroids and displayed heightened aggressiveness. Conversely, the NIS overexpression (OE) group exhibited suppressed abilities in invasion and colony formation.

Conclusion: Thyroid cancer cells exhibit diminished expression of NIS, and the invasion and maintenance of stem cells in thyroid cancer cells were hindered by NIS OE through the inhibition of the β-catenin/LEF-1 pathway. Further research is warranted to comprehensively assess this outcome, which holds promise as a potential targeted treatment for thyroid cancer.

Keywords: LEF-1; Papillary thyroid carcinoma; Sodium iodide symporter (NIS); β-Catenin.