文章：

IFN-α2在三阴性乳腺癌中对Schlafen家族基因的胞内调控作用

Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer

原文发布日期：30 November 2023

DOI: 10.3390/cancers15235658

类型: Article

开放获取: 是

英文摘要：

Triple-negative breast cancer (TNBC) has a poor prognosis and no targeted therapy for treatment. The Schlafen gene family, particularly SLFN12, critically mediates TNBC biology. Higher expression of SLFN12 correlates with decreased TNBC viability and increased chemosensitivity and patient survival, yet no treatment is known to upregulate SLFN12 in TNBC. We hypothesized that Interferon-α (IFN-α2) upregulates SLFN12 in TNBC, subsequently reducing cell viability. We utilized short hairpin adenovirus to knockout SLFN12 (AdvShSLFN12) in MDA-MB-231, Hs-578T, and BT-549 TNBC cells. Cells were treated with AdvShSLFN12 and IFN-α2. After treatment, TNBC cell viability, SLFN family mRNA, and protein expression were analyzed. Treating TNBC cells with IFN-α2 increased SLFN12 expression and reduced cell viability. However, when AdvShSLFN12 knocked down SLFN12 during IFN-α2 treatment, TNBC cell viability was still reduced. We, therefore, investigated the potential involvement of other SLFN members IFN-α2 effects on cell viability. IFN-α2 increased SLFN5, SLFN12-Like, and SLFN14 but not SLFN11 or SLFN13. During AdvShSLFN12 + IFN-α2 treatment, the expressions of SLFN5, SLFN12-Like, and SLFN14 further increased. However, when siRNA knocked down SLFN5, SLFN12-Like, and SLFN14, the IFN-α2 reduction in viability was blunted. Although the interpretation of these results may be limited by the potential interactions between different siRNAs, these data suggest a complex regulatory signaling cascade among SLFN family members. Targeting this cascade to manipulate SLFN levels may, in the future, offer the potential to manipulate the chemosensitivity of TNBC tumors.

摘要翻译： 

三阴性乳腺癌（TNBC）预后较差，且缺乏靶向治疗方法。Schlafen基因家族，特别是SLFN12，在TNBC的生物学过程中起着关键介导作用。SLFN12的高表达与TNBC细胞活力降低、化疗敏感性增强以及患者生存率提高相关，但目前尚无已知治疗方法能在TNBC中上调SLFN12。我们假设干扰素-α（IFN-α2）可上调TNBC中SLFN12的表达，从而降低细胞活力。本研究利用短发夹腺病毒在MDA-MB-231、Hs-578T和BT-549三种TNBC细胞系中敲除SLFN12（AdvShSLFN12），并对细胞进行AdvShSLFN12与IFN-α2联合处理。处理后检测TNBC细胞活力、SLFN家族mRNA及蛋白表达水平。结果显示，IFN-α2处理能上调SLFN12表达并降低TNBC细胞活力；然而在IFN-α2处理同时使用AdvShSLFN12敲低SLFN12后，TNBC细胞活力仍持续下降。因此我们进一步探究了其他SLFN家族成员可能参与IFN-α2调控细胞活力的机制。实验发现IFN-α2可上调SLFN5、SLFN12样蛋白及SLFN14的表达，但对SLFN11和SLFN13无显著影响。在AdvShSLFN12与IFN-α2联合处理期间，SLFN5、SLFN12样蛋白及SLFN14的表达进一步升高。而当使用siRNA敲低SLFN5、SLFN12样蛋白及SLFN14后，IFN-α2对细胞活力的抑制作用明显减弱。尽管不同siRNA之间潜在的相互作用可能影响结果解读，但这些数据提示SLFN家族成员间存在复杂的级联调控信号通路。未来通过靶向该调控级联来操纵SLFN表达水平，可能为调控TNBC肿瘤化疗敏感性提供新策略。

原文链接：

Schlafen Family Intra-Regulation by IFN-α2 in Triple-Negative Breast Cancer