PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p.
PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p.
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DOI：
10.18632/oncotarget.15213
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发表时间：
2017-02-28
期刊：
影响因子：
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通讯作者：
Deaglio S
中科院分区：
文献类型：
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作者：
Audrito V;Serra S;Stingi A;Orso F;Gaudino F;Bologna C;Neri F;Garaffo G;Nassini R;Baroni G;Rulli E;Massi D;Oliviero S;Piva R;Taverna D;Mandalà M;Deaglio S
PD-L1由具有不利结局的转移性黑色素瘤（MM）患者亚组表达。其表达在对BRAF或MEK抑制剂（BRAFi或MEKi）具有抗性的细胞中增加。然而，PD-L1表达的功能和调节仍然不完全清楚。在产生BRAFi和MEKi抗性细胞系后，我们观察到PD-L1表达的显著上调。这些细胞的特征在于共同的基因表达谱，其中涉及细胞运动的基因上调。一致的是，在体外，它们显示出显著增加的侵袭性。这种表型部分由PD-L1控制，如沉默分子后所确定的。PD-L1的上调是由于miR-17- 5 p控制的转录后事件，其与PD-L1 mRNA呈负相关。使用荧光素酶报告基因测定证明了miR-17- 5 p与PD-L1 mRNA的3 '-UTR之间的直接结合。在80例接受BRAFi或MEKi治疗的BRAF突变MM患者的队列中，在不存在免疫浸润的情况下PD-L1的组成型表达定义了预后最差的患者亚组。此外，在转移性病变对BRAFi或MEKi产生耐药性后，组织活检中PD-L1表达增加。最后，PD-L1+病变患者的血浆miR-17- 5 p水平高于PD-L1-病变患者。总之，我们的研究结果表明，PD-L1表达诱导黑色素瘤细胞更具侵略性的行为。我们还表明，BRAFi或MEKi耐药细胞中PD-L1上调部分是由于涉及miR-17- 5 p的转录后机制，这表明miR-17- 5 p可用作转移性病变PD-L1表达的标志物，并最终预测对BRAFi或MEKi的反应。
PD-L1 is expressed by a subset of patients with metastatic melanoma (MM) with an unfavorable outcome. Its expression is increased in cells resistant to BRAF or MEK inhibitors (BRAFi or MEKi). However, the function and regulation of expression of PD-L1 remain incompletely understood. After generating BRAFi- and MEKi-resistant cell lines, we observed marked up-regulation of PD-L1 expression. These cells were characterized by a common gene expression profile with up-regulation of genes involved in cell movement. Consistently, in vitro they showed significantly increased invasive properties. This phenotype was controlled in part by PD-L1, as determined after silencing the molecule. Up-regulation of PD-L1 was due to post-transcriptional events controlled by miR-17-5p, which showed an inverse correlation with PD-L1 mRNA. Direct binding between miR-17-5p and the 3’-UTR of PD-L1 mRNA was demonstrated using luciferase reporter assays. In a cohort of 80 BRAF-mutated MM patients treated with BRAFi or MEKi, constitutive expression of PD-L1 in the absence of immune infiltrate, defined the patient subset with the worst prognosis. Furthermore, PD-L1 expression increased in tissue biopsies after the metastatic lesions became resistant to BRAFi or MEKi. Lastly, plasmatic miR-17-5p levels were higher in patients with PD-L1+ than PD-L1- lesions. In conclusion, our findings indicate that PD-L1 expression induces a more aggressive behavior in melanoma cells. We also show that PD-L1 up-regulation in BRAFi or MEKi-resistant cells is partly due to post-transcriptional mechanisms that involve miR-17-5p, suggesting that miR-17-5p may be used as a marker of PD-L1 expression by metastatic lesions and ultimately a predictor of responses to BRAFi or MEKi.