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Abstract：
Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20-30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (miR-223, miR-155, miR-200b, miR-130b) and target genes (FLT1, PRDM1 and SAV1) in 35 ccRCC patients. High levels of miR-223 and low levels of FLT1, SAV1 and PRDM1 were associated with worse overall survival (OS), and combined miR-223 + SAV1 levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (FLT1) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (PRDM1) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect miR-155 we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation.
摘要：
近年来，舒尼替尼大大提高了透明细胞肾细胞癌（ccRCC）患者的生存率。然而,20-30%的治疗患者没有反应。为了鉴定与反应相关的miRNA和基因，比较了应答者和非应答者ccRCC患者的活检结果.使用整合的转录组学分析，我们鉴定了37个miRNAs和60个各自的靶基因，与NF-κB显著相关，PI3K-Akt和MAPK途径。我们验证了miRNA的表达（miR-223，miR-155，miR-200b，35例ccRCC患者的miR-130b）和靶基因（FLT1，PRDM1和SAV1）。高水平的miR-223和低水平的FLT1，SAV1和PRDM1与较差的总生存期（OS）相关。和组合的miR-223+SAV1水平区分应答者和非应答者(AUC=0.92)。使用170例ccRCC患者的免疫组织化学染色，VEGFR1（FLT1）表达与治疗反应相关，组织学分级和RECIST（实体瘤反应评估标准）评分，而SAV1和BLIMP1（PRDM1）与异时转移性疾病相关。使用原位杂交（ISH）检测miR-155，我们观察到无反应者的肿瘤细胞表达更高，和非肿瘤细胞表达随着组织学分级的增加。总之,我们使用整合的miRNA-靶基因分析进行的初步分析在ccRCC患者中发现了几种新的生物标志物,这些生物标志物肯定值得进一步研究.
