The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization

The metal cation symporter ZIP8 (SLC39A8) is a transmembrane protein that imports the essential micronutrients iron, manganese, and zinc, as well as heavy toxic metal cadmium (Cd). It has been recently suggested that selenium (Se), another essential micronutrient that has long been known for its rol...

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Autores principales:	Zhan-Ling Liang, Heng Wee Tan, Jia-Yi Wu, Xu-Li Chen, Xiu-Yun Wang, Yan-Ming Xu, Andy T. Y. Lau
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cadmium cytotoxicity cancer therapy cisplatin ICP-MS nonsynonymous mutation selenium homeostasis Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/8e5a1d1a512f4acfb3d495d92130424b
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spelling	oai:doaj.org-article:8e5a1d1a512f4acfb3d495d92130424b2021-11-11T16:52:35ZThe Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization10.3390/ijms2221113991422-00671661-6596https://doaj.org/article/8e5a1d1a512f4acfb3d495d92130424b2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11399https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The metal cation symporter ZIP8 (SLC39A8) is a transmembrane protein that imports the essential micronutrients iron, manganese, and zinc, as well as heavy toxic metal cadmium (Cd). It has been recently suggested that selenium (Se), another essential micronutrient that has long been known for its role in human health and cancer risk, may also be transported by the ZIP8 protein. Several mutations in the ZIP8 gene are associated with the aberrant ion homeostasis of cells and can lead to human diseases. However, the intricate relationships between ZIP8 mutations, cellular Se homeostasis, and human diseases (including cancers and illnesses associated with Cd exposure) have not been explored. To further verify if ZIP8 is involved in cellular Se transportation, we first knockout (KO) the endogenous expression of ZIP8 in the HeLa cells using the CRISPR/Cas9 system. The elimination of ZIP8 expression was examined by PCR, DNA sequencing, immunoblot, and immunofluorescence analyses. Inductively coupled plasma mass spectrometry indicated that reduced uptake of Se, along with other micronutrients and Cd, was observed in the ZIP8-KO cells. In contrast, when ZIP8 was overexpressed, increased Se uptake could be detected in the ZIP8-overexpressing cells. Additionally, we found that ZIP8 with disease-associated single-point mutations G38R, G204C, and S335T, but not C113S, showed reduced Se transport ability. We then evaluated the potential of Se on Cd cytotoxicity prevention and therapy of cancers. Results indicated that Se could suppress Cd-induced cytotoxicity via decreasing the intracellular Cd transported by ZIP8, and Se exhibited excellent anticancer activity against not all but only selected cancer cell lines, under restricted experimental conditions. Moreover, clinical-based bioinformatic analyses revealed that up-regulated ZIP8 gene expression was common across multiple cancer types, and selenoproteins that were significantly co-expressed with ZIP8 in these cancers had been identified. Taken together, this study concludes that ZIP8 is an important protein in modulating cellular Se levels and provides insights into the roles of ZIP8 and Se in disease prevention and therapy.Zhan-Ling LiangHeng Wee TanJia-Yi WuXu-Li ChenXiu-Yun WangYan-Ming XuAndy T. Y. LauMDPI AGarticlecadmium cytotoxicitycancer therapycisplatinICP-MSnonsynonymous mutationselenium homeostasisBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11399, p 11399 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cadmium cytotoxicity cancer therapy cisplatin ICP-MS nonsynonymous mutation selenium homeostasis Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	cadmium cytotoxicity cancer therapy cisplatin ICP-MS nonsynonymous mutation selenium homeostasis Biology (General) QH301-705.5 Chemistry QD1-999 Zhan-Ling Liang Heng Wee Tan Jia-Yi Wu Xu-Li Chen Xiu-Yun Wang Yan-Ming Xu Andy T. Y. Lau The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization
description	The metal cation symporter ZIP8 (SLC39A8) is a transmembrane protein that imports the essential micronutrients iron, manganese, and zinc, as well as heavy toxic metal cadmium (Cd). It has been recently suggested that selenium (Se), another essential micronutrient that has long been known for its role in human health and cancer risk, may also be transported by the ZIP8 protein. Several mutations in the ZIP8 gene are associated with the aberrant ion homeostasis of cells and can lead to human diseases. However, the intricate relationships between ZIP8 mutations, cellular Se homeostasis, and human diseases (including cancers and illnesses associated with Cd exposure) have not been explored. To further verify if ZIP8 is involved in cellular Se transportation, we first knockout (KO) the endogenous expression of ZIP8 in the HeLa cells using the CRISPR/Cas9 system. The elimination of ZIP8 expression was examined by PCR, DNA sequencing, immunoblot, and immunofluorescence analyses. Inductively coupled plasma mass spectrometry indicated that reduced uptake of Se, along with other micronutrients and Cd, was observed in the ZIP8-KO cells. In contrast, when ZIP8 was overexpressed, increased Se uptake could be detected in the ZIP8-overexpressing cells. Additionally, we found that ZIP8 with disease-associated single-point mutations G38R, G204C, and S335T, but not C113S, showed reduced Se transport ability. We then evaluated the potential of Se on Cd cytotoxicity prevention and therapy of cancers. Results indicated that Se could suppress Cd-induced cytotoxicity via decreasing the intracellular Cd transported by ZIP8, and Se exhibited excellent anticancer activity against not all but only selected cancer cell lines, under restricted experimental conditions. Moreover, clinical-based bioinformatic analyses revealed that up-regulated ZIP8 gene expression was common across multiple cancer types, and selenoproteins that were significantly co-expressed with ZIP8 in these cancers had been identified. Taken together, this study concludes that ZIP8 is an important protein in modulating cellular Se levels and provides insights into the roles of ZIP8 and Se in disease prevention and therapy.
format	article
author	Zhan-Ling Liang Heng Wee Tan Jia-Yi Wu Xu-Li Chen Xiu-Yun Wang Yan-Ming Xu Andy T. Y. Lau
author_facet	Zhan-Ling Liang Heng Wee Tan Jia-Yi Wu Xu-Li Chen Xiu-Yun Wang Yan-Ming Xu Andy T. Y. Lau
author_sort	Zhan-Ling Liang
title	The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization
title_short	The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization
title_full	The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization
title_fullStr	The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization
title_full_unstemmed	The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization
title_sort	impact of zip8 disease-associated variants g38r, c113s, g204c, and s335t on selenium and cadmium accumulations: the first characterization
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/8e5a1d1a512f4acfb3d495d92130424b
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The Impact of ZIP8 Disease-Associated Variants G38R, C113S, G204C, and S335T on Selenium and Cadmium Accumulations: The First Characterization

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