SBP1 通过 TXN/NIS 通路促进甲状腺癌的肿瘤发生。
SBP1 promotes tumorigenesis of thyroid cancer through TXN/NIS pathway.
机构信息
Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China.
Department of General Surgery, Xi'an Central Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710003, China.
出版信息
Mol Med. 2023 Sep 8;29(1):121. doi: 10.1186/s10020-023-00700-y.
BACKGROUND
As the tissue with the highest selenium content in the body, the occurrence and development of thyroid cancer are closely related to selenium and selenoproteins. Selenium-binding protein 1 (SBP1) has been repeatedly implicated in several cancers, but its role and molecular mechanisms in thyroid cancer remains largely undefined.
METHODS
The expression of SBP1, sodium/iodide symporter (NIS) and thioredoxin (TXN) were analyzed in clinical samples and cell lines. Cell counting kit-8 (CCK-8) and tube formation assays were used to analyze the cell viability and tube formation of cells. Immunofluorescence was used to determine the expression of the NIS. Co-immunoprecipitation (Co-IP) assay was carried out to verify the interaction of SBP1 with TXN. The mouse xenograft experiment was performed to investigate the growth of thyroid cancer cells with SBP1 knockdown in vivo.
RESULTS
SBP1 was significantly increased in human thyroid cancer tissues and cells, especially in anaplastic thyroid cancer. Overexpression of SBP1 promoted FTC-133 cell proliferation, and the culture supernatant of SBP1-overexpression FTC-133 cells promoted tube formation of human retinal microvascular endothelial cells. Knockdown of SBP1, however, inhibited cell proliferation and tube formation. Furthermore, overexpression of SBP1 inhibited cellular differentiation of differentiated thyroid cancer cell line FTC-133, as indicated by decreased expression of thyroid stimulating hormone receptors, thyroglobulin and NIS. Knockdown of SBP1, however, promoted differentiation of BHT101 cells, an anaplastic thyroid cancer cell line. Notably, TXN, a negative regulator of NIS, was found to be significantly upregulated in human thyroid cancer tissues, and it was positively regulated by SBP1. Co-IP assay implied a direct interaction of SBP1 with TXN. Additionally, TXN overexpression reversed the effect of SBP1 knockdown on BHT101 cell viability, tube formation and cell differentiation. An in vivo study found that knockdown of SBP1 promoted the expression of thyroid stimulating hormone receptors, thyroglobulin and NIS, as well as inhibited the growth and progression of thyroid cancer tumors.
CONCLUSION
SBP1 promoted tumorigenesis and dedifferentiation of thyroid cancer through positively regulating TXN.
背景
作为体内硒含量最高的组织，甲状腺癌的发生和发展与硒和硒蛋白密切相关。硒结合蛋白 1（SBP1）已在多种癌症中反复被提及，但它在甲状腺癌中的作用和分子机制在很大程度上仍未确定。
方法
分析了临床样本和细胞系中 SBP1、钠/碘转运体（NIS）和硫氧还蛋白（TXN）的表达。细胞计数试剂盒-8（CCK-8）和管形成实验用于分析细胞活力和细胞管形成。免疫荧光用于确定 NIS 的表达。共免疫沉淀（Co-IP）实验用于验证 SBP1 与 TXN 的相互作用。进行小鼠异种移植实验以研究体内敲低 SBP1 对甲状腺癌细胞生长的影响。
结果
SBP1 在人甲状腺癌组织和细胞中显著增加，特别是在间变性甲状腺癌中。SBP1 的过表达促进 FTC-133 细胞增殖，而过表达 SBP1 的 FTC-133 细胞的培养上清液促进人视网膜微血管内皮细胞的管形成。然而，SBP1 的敲低抑制了细胞增殖和管形成。此外，过表达 SBP1 抑制分化型甲状腺癌细胞系 FTC-133 的细胞分化，表现为促甲状腺激素受体、甲状腺球蛋白和 NIS 的表达减少。然而，SBP1 的敲低促进了间变性甲状腺癌细胞系 BHT101 的分化。值得注意的是，TXN，一种 NIS 的负调节剂，在人甲状腺癌组织中显著上调，并且受 SBP1 的正调控。Co-IP 实验暗示 SBP1 与 TXN 之间存在直接相互作用。此外，TXN 的过表达逆转了 SBP1 敲低对 BHT101 细胞活力、管形成和细胞分化的影响。一项体内研究发现，SBP1 的敲低促进了促甲状腺激素受体、甲状腺球蛋白和 NIS 的表达，同时抑制了甲状腺癌肿瘤的生长和进展。
结论
SBP1 通过正向调节 TXN 促进甲状腺癌细胞的肿瘤发生和去分化。
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