Type 1 iodothyronine deiodinase (DIO1) contributes to deiodination of 3,5,3’,5’-tetraiodo-L-thyronine (thyroxine, T4) yielding of 3,5,3’-triiodothyronine (T3), a powerful regulator of cell differentiation, proliferation, and metabolism. Our previous work showed that loss of DIO1 enhances proliferation and migration of renal cancer cells. However, the global effects of DIO1 expression in various tissues affected by cancer remain unknown. Here, the effects of stable DIO1 re-expression were analyzed on the proteome of renal cancer cells, followed by quantitative real-time PCR validation in two renal cancer-derived cell lines. DIO1-induced changes in intracellular concentrations of thyroid hormones were quantified by L-MS/MS and correlations between expression of DIO1 and potential target genes were determined in tissue samples from renal cancer patients. Stable re-expression of DIO1, resulted in 26 downregulated proteins while 59 proteins were overexpressed in renal cancer cells. The ‘downregulated’ group consisted mainly of oncoproteins (e.g. STAT3, ANPEP, TGFBI, TGM2) that promote proliferation, migration and invasion. Furthermore, DIO1 re-expression enhanced concentrations of two subunits of thyroid hormone transporter (SLC7A5, SLC3A2), enzymes of key pathways of cellular energy metabolism (e.g. TKT, NAMPT, IDH2), sex steroid metabolism and anti-oxidative response (AKR1C2, AKR1B10). DIO1 expression resulted in elevated intracellular concentration of T4. Expression of DIO1-affected genes strongly correlated with DIO1 transcript levels in tissue samples from renal cancer patients as well as with their poor survival. This first study addressing effects of deiodinase re-expression on proteome of cancer cells demonstrates that induced DIO1 re-expression in renal cancer robustly downregulates oncoproteins, affects key metabolic pathways, and triggers proteins involved in anti-oxidative protection. This data supports the notion that suppressed DIO1 expression and changes in local availability of thyroid hormones might favor a shift from a differentiated to a more proliferation-prone state of cancer tissues and cell lines.

1型碘甲状腺素脱碘酶（DIO1）有助于3,5,3'，5'-四碘-L-甲状腺素（甲状腺素，T4）的碘化作用，产生3,5,3'-三碘甲状腺素（T3），一种强大的细胞调节剂分化，增殖和新陈代谢。我们以前的工作表明，DIO1的丢失会增强肾癌细胞的增殖和迁移。但是，DIO1表达在受癌症影响的各种组织中的总体作用仍然未知。在此，分析了稳定的DIO1重新表达对肾癌细胞蛋白质组的影响，然后在两种源自肾癌的细胞系中进行了实时定量PCR验证。通过L-MS / MS定量测定DIO1诱导的甲状腺激素细胞内浓度的变化，并测定肾癌患者组织样品中DIO1的表达与潜在靶基因之间的相关性。DIO1的稳定重新表达，导致26种蛋白下调，而59种蛋白在肾癌细胞中过表达。“下调”组主要由促进增殖，迁移和侵袭的癌蛋白（例如STAT3，ANPEP，TGFBI，TGM2）组成。此外，DIO1的重新表达增强了甲状腺激素转运蛋白的两个亚基（SLC7A5，SLC3A2），细胞能量代谢关键途径的酶（例如TKT，NAMPT，IDH2），性类固醇代谢和抗氧化反应（AKR1C2，AKR1B10）的浓度）。DIO1表达导致T4的细胞内浓度升高。DIO1受影响的基因的表达与肾癌患者组织样本中DIO1转录水平及其生存不良密切相关。这项针对脱碘酶重新表达对癌细胞蛋白质组的影响的第一项研究表明，在肾癌中诱导的DIO1重新表达强烈下调癌蛋白，影响关键的代谢途径并触发参与抗氧化保护的蛋白。该数据支持这样的观点，即抑制DIO1表达和甲状腺激素局部可用性的变化可能有助于从癌组织和细胞系的分化状态转变为更易于增殖的状态。这项针对脱碘酶重新表达对癌细胞蛋白质组的影响的第一项研究表明，在肾癌中诱导的DIO1重新表达强烈下调癌蛋白，影响关键的代谢途径并触发参与抗氧化保护的蛋白。该数据支持这样的观念，即抑制DIO1表达和甲状腺激素的局部可利用性的改变可能有助于从癌组织和细胞系的分化状态转变为更易于增殖的状态。这项针对脱碘酶重新表达对癌细胞蛋白质组的影响的第一项研究表明，在肾癌中诱导的DIO1重新表达强烈下调癌蛋白，影响关键的代谢途径并触发参与抗氧化保护的蛋白。该数据支持这样的观念，即抑制DIO1表达和甲状腺激素的局部可利用性的改变可能有助于从癌组织和细胞系的分化状态转变为更易于增殖的状态。