Pich Christine, Teiti Iotefa, Sarrabayrouse Guillaume, Gallardo Franck, Gence Rémi, Tilkin-Mariamé Anne-Françoise
INSERM UMR 1037, CRCT, Toulouse FR-31037, France.
Université Paul Sabatier, Toulouse FR-31062, France.
PLoS One. 2016 Feb 1;11(2):e0148095. doi: 10.1371/journal.pone.0148095. eCollection 2016.
CD70 is a costimulatory molecule member of the Tumor Necrosis Factor family that is expressed on activated immune cells. Its ectopic expression has been described in several types of cancer cells including lymphomas, renal cell carcinomas and glioblastomas. We have recently described its expression in a part of tumor cells from the vast majority of melanoma biopsies and human melanoma cell lines, and found that CD70 expression decreased over time as the disease progressed. Here, we show that RhoA, BRAF and Mitogen Activating Protein Kinase pathways are involved in the positive transcriptional regulation of CD70 expression in melanomas. Interestingly, the clinical inhibitor of the common BRAF V600E/D variants, Vemurafenib (PLX-4032), which is currently used to treat melanoma patients with BRAF V600E/D-mutated metastatic melanomas, decreased CD70 expression in human CD70+ melanoma cell lines. This decrease was seen in melanoma cells both with and without the BRAFV600E/D mutation, although was less efficient in those lacking the mutation. But interestingly, by silencing CD70 in CD70+ melanoma cell lines we show that PLX-4032-induced melanoma cell killing and its inhibitory effect on MAPK pathway activation are unaffected by CD70 expression. Consequently, our work demonstrates that CD70 ectopic expression in melanomas is not a valuable biomarker to predict tumor cells sensitivity to BRAF V600 inhibitors.
CD70是肿瘤坏死因子家族的共刺激分子成员，在活化的免疫细胞上表达。其异位表达已在包括淋巴瘤、肾细胞癌和胶质母细胞瘤在内的多种癌细胞中被描述。我们最近描述了它在绝大多数黑色素瘤活检组织和人黑色素瘤细胞系的部分肿瘤细胞中的表达，并发现随着疾病进展，CD70表达随时间下降。在这里，我们表明RhoA、BRAF和丝裂原活化蛋白激酶途径参与黑色素瘤中CD70表达的正转录调控。有趣的是，目前用于治疗BRAF V600E/D突变的转移性黑色素瘤患者的常见BRAF V600E/D变体的临床抑制剂维莫非尼（PLX-4032），降低了人CD70+黑色素瘤细胞系中CD70的表达。在有和没有BRAFV600E/D突变的黑色素瘤细胞中均观察到这种下降，尽管在缺乏该突变的细胞中效率较低。但有趣的是，通过在CD70+黑色素瘤细胞系中沉默CD70，我们表明PLX-4032诱导的黑色素瘤细胞杀伤及其对MAPK途径激活的抑制作用不受CD70表达的影响。因此，我们的工作表明黑色素瘤中CD70的异位表达不是预测肿瘤细胞对BRAF V600抑制剂敏感性的有价值的生物标志物。
