Breunig Christian, Pahl Jens, Küblbeck Moritz, Miller Matthias, Antonelli Daniela, Erdem Nese, Wirth Cornelia, Will Rainer, Bott Alexander, Cerwenka Adelheid, Wiemann Stefan
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Innate Immunity Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cell Death Dis. 2017 Aug 3;8(8):e2973. doi: 10.1038/cddis.2017.364.
Aggressive breast cancer is associated with poor patient outcome and characterized by the development of tumor cell variants that are able to escape from control of the immune system or are resistant to targeted therapies. The complex molecular mechanisms leading to immune escape and therapy resistance are incompletely understood. We have previously shown that high miR-519a-3p levels are associated with poor survival in breast cancer. Here, we demonstrate that miR-519a-3p confers resistance to apoptosis induced by TRAIL, FasL and granzyme B/perforin by interfering with apoptosis signaling in breast cancer cells. MiR-519a-3p diminished the expression of its direct target genes for TRAIL-R2 (TNFRSF10B) and for caspase-8 (CASP8) and its indirect target gene for caspase-7 (CASP7), resulting in reduced sensitivity and tumor cell apoptosis in response to apoptotic stimuli. Furthermore, miR-519a-3p impaired tumor cell killing by natural killer (NK) cells via downregulation of the NKG2D ligands ULBP2 and MICA on the surface of tumor cells that are crucial for the recognition of these tumor cells by NK cells. We determined that miR-519a-3p was overexpressed in more aggressive mutant TP53 breast cancer that was associated with poor survival. Furthermore, low levels of TRAIL-R2, caspase-7 and caspase-8 correlated with poor survival, suggesting that the inhibitory effect of miR-519a-3p on TRAIL-R2 and caspases may have direct clinical relevance in lowering patient's prognosis. In conclusion, we demonstrate that miR-519a-3p is a critical factor in mediating resistance toward cancer cell apoptosis and impairing tumor cell recognition by NK cells. This joint regulation of apoptosis and immune cell recognition through miR-519a-3p supports the hypothesis that miRNAs are key regulators of cancer cell fate, facilitating cancer progression and evasion from immunosurveillance at multiple and interconnected levels.
侵袭性乳腺癌与患者预后不良相关，其特征是肿瘤细胞变体的出现，这些变体能够逃避免疫系统的控制或对靶向治疗产生抗性。导致免疫逃逸和治疗抗性的复杂分子机制尚未完全明确。我们之前已经表明，高 miR-519a-3p 水平与乳腺癌患者的不良生存相关。在此，我们证明 miR-519a-3p 通过干扰乳腺癌细胞中的凋亡信号传导，赋予对 TRAIL、FasL 和颗粒酶 B/穿孔素诱导的凋亡的抗性。MiR-519a-3p 降低了其 TRAIL-R2（TNFRSF10B）和半胱天冬酶 -8（CASP8）的直接靶基因以及半胱天冬酶 -7（CASP7）的间接靶基因的表达，导致对凋亡刺激的敏感性降低和肿瘤细胞凋亡减少。此外，miR-519a-3p 通过下调肿瘤细胞表面对自然杀伤（NK）细胞识别这些肿瘤细胞至关重要的 NKG2D 配体 ULBP2 和 MICA，损害了 NK 细胞对肿瘤细胞的杀伤作用。我们确定 miR-519a-3p 在更具侵袭性的突变型 TP53 乳腺癌中过表达，这与不良生存相关。此外，低水平的 TRAIL-R2、半胱天冬酶 -7 和半胱天冬酶 -8 与不良生存相关，表明 miR-519a-3p 对 TRAIL-R2 和半胱天冬酶的抑制作用可能在降低患者预后方面具有直接临床相关性。总之，我们证明 miR-519a-3p 是介导癌细胞凋亡抗性和损害 NK 细胞对肿瘤细胞识别的关键因素。通过 miR-519a-3p 对凋亡和免疫细胞识别的这种联合调节支持了这样的假设，即 microRNA 是癌细胞命运的关键调节因子，在多个相互关联的水平上促进癌症进展和逃避免疫监视。
