Khella Heba W Z, Butz Henriett, Ding Qiang, Rotondo Fabio, Evans Kenneth R, Kupchak Peter, Dharsee Moyez, Latif Ashraf, Pasic Maria D, Lianidou Evi, Bjarnason Georg A, Yousef George M
Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Department of Laboratory Medicine, and the Keenan Research Centre for Biomedical Science at the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Mol Ther. 2015 Nov;23(11):1748-1758. doi: 10.1038/mt.2015.129. Epub 2015 Jul 23.
Sunitinib is a multitargeting tyrosine kinase inhibitor used for metastatic renal cancer. There are no biomarkers that can predict sunitinib response. Such markers are needed to avoid administration of costly medication with side effects to patients who would not benefit from it. We compared global miRNA expression between patients with a short (≤12 months) versus prolonged (>12 months) progression-free survival (PFS) under sunitinib as first-line therapy for metastatic renal cell carcinoma. We identified a number of differentially expressed miRNAs and developed miRNA statistical models that can accurately distinguish between the two groups. We validated our models in the discovery set and an independent set of 57 patients. Target prediction and pathway analysis showed that these miRNAs are involved in vascular endothelial growth factor (VEGF), TGFβ, and mammalian target of rapamycin (mTOR)-mediated signaling and cell-cell communication. We tested the effect of these miRNAs on cellular proliferation and angiogenesis. We validated the negative correlation between miR-221 and its target, VEGFR2.miR-221 overexpression was associated with a poor PFS while its target, VEGFR2 was associated with longer survival. Gain of function experiments showed that miR-221 and miR-222 decreased angiogenesis and cellular proliferation in human umbilical vein endothelial cells (HUVEC) while increasing cellular proliferation in ACHN cells. miRNAs represent potential predictive markers for sunitinib response.
舒尼替尼是一种用于转移性肾癌的多靶点酪氨酸激酶抑制剂。目前尚无能够预测舒尼替尼疗效的生物标志物。需要此类标志物来避免对无法从中获益的患者使用昂贵且有副作用的药物。我们比较了接受舒尼替尼一线治疗的转移性肾细胞癌患者中无进展生存期（PFS）较短（≤12个月）与较长（>12个月）者之间的整体miRNA表达情况。我们鉴定出了一些差异表达的miRNA，并建立了能够准确区分这两组患者的miRNA统计模型。我们在发现集和一组57例患者的独立队列中验证了我们的模型。靶标预测和通路分析表明，这些miRNA参与血管内皮生长因子（VEGF）、转化生长因子β（TGFβ）和雷帕霉素靶蛋白（mTOR）介导的信号传导及细胞间通讯。我们测试了这些miRNA对细胞增殖和血管生成的影响。我们验证了miR-221与其靶标VEGFR2之间的负相关性。miR-221过表达与较差的PFS相关，而其靶标VEGFR2则与更长的生存期相关。功能获得实验表明，miR-221和miR-222可降低人脐静脉内皮细胞（HUVEC）的血管生成和细胞增殖，同时增加ACHN细胞的细胞增殖。miRNA代表了舒尼替尼疗效的潜在预测标志物。
