硒结合蛋白SBP1通过抑制xCT转录逆转乳腺癌对表柔比星耐药的机制

Although epirubicin (EPI) is one of the most effective drugs against breast cancer, the acquired resistance of breast cancer cells to EPI is becoming a major obstacle for successful therapy. In the established EPI-resistant breast cancer cells, we found Selenium Binding Protein 1 (SBP1) was indeed involved in the development of acquired resistance of breast cancer cells to EPI. Furthermore, we identified a novel function for SBP1 in the regulation of the mRNA and protein expression of xCT, a light subunit conferring transport and substrate specificity of Xc- cystine/glutamate antiporter which plays a rate-limiting role in the biosynthesis of glutathione. In addition, we revealed that SBP1 repressed the phosphorylation levels of transcription factor STAT1, while STAT1 positively regulated xCT protein expression. Bioinformatics analysis indicated that there are several potential binding site of STAT1 in xCT promote. Collectively, these findings led us to the hypothesis that SBP1 inhibits the transcription of xCT via STAT1. Therefore, this project aims to investigate the molecular mechanism underlying STAT1-mediated transcription regulation of xCT by SBP1 in breast cancer, finally verifying the potential role for SBP1/STAT1/xCT signaling in restoring the sensitivity of breast cancer to EPI. These findings will provide mechanistic insights and identify novel therapeutic targets for cracking the hard nuts of the acquired resistance of breast cancer to EPI.

表柔比星作为治疗乳腺癌最有效的化学治疗药物之一,但继发性耐药的产生严重制约了该药物在临床上的应用。我们在继发性耐药的乳腺癌细胞中发现,硒结合蛋白SBP1参与了表柔比星耐药机制的产生。进一步研究,发现了SBP1新的生物学功能,即SBP1对在谷胱甘肽合成限速环节起关键作用的胱氨酸/谷氨酸反向转运体亚基xCT的mRNA和蛋白存在调控作用,提示SBP1抑制xCT转录。此外,我们发现SBP1特异性地抑制转录因子STAT1的磷酸化,而STAT1对xCT存在正向调控作用;而且发现xCT启动子上存在STAT1的潜在结合位点。因此,本项目拟采用基因干扰、启动子定点突变和ChIP等实验技术,旨在回答SBP1如何通过STAT1直接转录调控xCT这一关键科学问题。本项目的实施将阐明SBP1/STAT1/xCT通路对表柔比星药物敏感性的影响,为确立SBP1作为逆转乳腺癌表柔比星耐药的新靶点提供科学依据。

硒结合蛋白1（Selenium-binding protein 1；SELENBP1 or SBP1）在多种实体瘤肿瘤组织中显著下调甚至缺失，且与肿瘤患者患者预后呈正相关，提示该分子在肿瘤的发生发展中可能发挥着抑癌基因功能。然而，SELENBP1在乳腺癌、膀胱癌中的表达特征、对常见化疗药物表柔比星药物敏感性的影响、抑制肿瘤细胞异常增殖的分子机制目前尚不清晰。. 在该项目中，我们发现：1）SELENBP1在Luminal A/B亚型乳腺癌中整体表达水平较高，但在Basal-like/Claudin-low亚型中表达水平最低，与雌/孕激素表达水平密切相关，提示雌/孕激素介导的信号通路可能对该蛋白存在正向调控作用；2）虽然SELENBP1异常表达的患者预后较差，但其表达水平在不同亚型中具有完全不同的预后预测作用；在Luminal亚型中，SELENBP1高表达的患者预后较差，然而在Basal-like/Claudin-low亚型中，低表达的患者预后较差；3）SELENBP1过表达能逆转乳腺癌对表柔比星的耐药，而这一作用可能并不依赖于谷胱甘肽过氧化物酶GPX1；4）SELENBP1过表达抑制了胱氨酸/谷氨酸反向转运体亚基xCT（SLC7A11）蛋白及mRNA表达，而过表达xCT使得乳腺癌细胞对表柔比星耐药，提示xCT可能参与了SELENBP1对表柔比星药物敏感性的影响；5）首次报道SELENBP1在膀胱癌肿瘤组织中广泛低表达或缺失，且其低表达的患者预后较差，而DNA甲基化可能是介导SELENBP1在该癌种中表达沉默的重要机制之一；6）SELENBP1过表达诱导肿瘤细胞发生G0/G1周期阻滞，而p21是该蛋白发挥抑制异常增殖功能的关键下游分子；7）SELENBP1特异性地抑制STAT1和c-Jun转录因子的磷酸化水平，而两者共同参与了SELENBP1对p21的转录调控。. 综上，我们从临床和基础研究中揭示了SELENBP1具有抑癌基因的特性，也具有评估肿瘤患者预后的生物标记物的潜力，为SELENBP1成为逆转乳腺癌表柔比星耐药、改善恶性肿瘤患者预后的新靶标提供了科学依据。

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