Chasing an intriguing biological question on the disparity of sodium iodide symporter (NIS, officially known as SLC5A5) expression and function in the clinical scenario of breast cancer, this study addresses key molecular defects involved. NIS in cancer patients has primarily been recorded to be a cytoplasmic protein, thus limiting the scope for targeted radio-iodine therapy. We developed NIS transgene-overexpressing MCF-7 breast cancer cells, and found a few clonal derivatives that show predominant expression of NIS in the plasma membrane. The majority of clones, however, showed cytosolic NIS expression over long passages. Cells expressing membranous NIS show unperturbed dynamic trafficking of NIS through secretory pathway organelles when compared to cells expressing cytoplasmic NIS or to parental cells. Further, treatment of cells expressing membranous NIS with specific glycosylation inhibitors highlighted the importance of inherent glycosylation processing and an 84 gene signature glycosylation RT-Profiler array revealed that clones expressing NIS in their membrane cluster separately compared to the other cells. We further confirm a role of three differentially expressed genes, i.e. MAN1B1, MAN1A1 and MAN2A1, in regulating NIS localization by RNA interference. Thus, this study shows the important role of mannosidase in N-glycosylation processing in order to correctly traffic NIS to the plasma membrane in breast cancer cells.This article has an associated First Person interview with the first author of the paper.

中文翻译：

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甘露糖糖基化是人乳腺癌细胞中NIS定位和功能不可或缺的步骤。

追寻有关碘化钠共转运蛋白（NIS，正式称为SLC5A5）在乳腺癌临床中的表达和功能差异的有趣的生物学问题，该研究解决了涉及的关键分子缺陷。癌症患者中的NIS主要被记录为细胞质蛋白，因此限制了靶向放射性碘治疗的范围。我们开发了NIS转基因过表达的MCF-7乳腺癌细胞，并发现了一些克隆衍生物，它们在细胞膜中显示NIS的主要表达。然而，大多数克隆在长时间的传代过程中显示出胞质NIS表达。与表达细胞质NIS的细胞或亲代细胞相比，表达膜性NIS的细胞通过分泌途径的细胞器显示出NIS的动态运输不受干扰。进一步，用特定的糖基化抑制剂处理表达膜性NIS的细胞强调了固有糖基化过程的重要性，并且84个基因签名的糖基化RT-Profiler阵列显示与其他细胞相比，在其膜簇中表达NIS的克隆分别存在。我们进一步证实了三个差异表达的基因，即MAN1B1，MAN1A1和MAN2A1，在通过RNA干扰调节NIS定位中的作用。因此，本研究显示了甘露糖苷酶在N-糖基化过程中的重要作用，以正确地将NIS转运到乳腺癌细胞的质膜中。