Department of Anatomy and Cell Biology, Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.
Int J Mol Sci. 2022 May 17;23(10):5604. doi: 10.3390/ijms23105604.
This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six primary kidney tumors with matching normal kidney tissues. The data in the five non-sarcomatoid ccRCC cell lines-RC2, CAKI-1, 786-0, RCC4, and RCC4/VHL-and in the four ccRCC with sarcomatoid differentiation-RCJ41T1, RCJ41T2, RCJ41M, and UOK-127-indicated that miR-17 and -19a were expressed at lower levels relative to miR-34a, -155, and -210. Compared with RPTEC normal epithelial cells, miR-34a, miR-155, and miR-210 were expressed at higher levels, independent of the sarcomatoid differentiation status and hypoxia-inducible factors 1α and 2α (HIFs) isoform expression. In the one chromophobe renal cell carcinoma cell line, namely, UOK-276 with sarcomatoid differentiation, and expressing tumor suppressor gene , miR-34a, which is a tumor suppressor gene, was expressed at higher levels than miR-210, -155, -17, and -19a. The pilot results generated in six tumor biopsies with matching normal kidney tissues indicated that while the expression of miR-17 and -19a were similar to the normal tissue expression profile, miR-210, -155, -and 34a were expressed at a higher level. To confirm that differences in the expression levels of the five miRs in the six tumor biopsies were statistically significant, the acquisition of a larger sample size is required. Data previously generated in ccRCC cell lines demonstrating that miR-210, miR-155, and HIFs are druggable targets using a defined dose and schedule of selenium-containing molecules support the concept that simultaneous and concurrent downregulation of miR-210, miR-155, and HIFs, which regulate target genes associated with increased tumor angiogenesis and drug resistance, may offer the potential for the development of a novel mechanism-based strategy for the treatment of patients with advanced ccRCC.
这项研究旨在定量检测 9 种透明细胞肾细胞癌（ccRCC）和 1 种嫌色细胞肾细胞癌细胞系在有和没有肉瘤样分化的情况下以及在 6 种具有匹配正常肾组织的原发性肾肿瘤中表达的 microRNA-17、-19a、-34a、-155 和 -210（miRs）的表达水平。在五个非肉瘤样 ccRCC 细胞系（RC2、CAKI-1、786-0、RCC4 和 RCC4/VHL）和四个具有肉瘤样分化的 ccRCC（RCJ41T1、RCJ41T2、RCJ41M 和 UOK-127）中，miR-17 和 -19a 的表达水平相对 miR-34a、-155 和 -210 较低。与 RPTEC 正常上皮细胞相比，miR-34a、miR-155 和 miR-210 的表达水平更高，与肉瘤样分化状态以及缺氧诱导因子 1α 和 2α（HIFs）同工型表达无关。在一个具有肉瘤样分化的嫌色细胞肾细胞癌细胞系 UOK-276 中，肿瘤抑制基因的表达水平较高，miR-34a 作为肿瘤抑制基因的表达水平高于 miR-210、-155、-17 和 -19a。在六个具有匹配正常肾组织的肿瘤活检中生成的初步结果表明，尽管 miR-17 和 -19a 的表达与正常组织表达谱相似，但 miR-210、-155 和 -34a 的表达水平更高。为了确认六个肿瘤活检中五个 miRs 的表达水平差异具有统计学意义，需要获得更大的样本量。先前在 ccRCC 细胞系中生成的数据表明，使用一定剂量和硒化合物分子的方案，miR-210、miR-155 和 HIFs 是可治疗的靶点，支持同时下调 miR-210、miR-155 和 HIFs 的概念，这些下调调节与增加肿瘤血管生成和药物耐药性相关的靶基因，可能为开发针对晚期 ccRCC 患者的新型基于机制的治疗策略提供潜力。
