Saleeb Rola, Kim Sung Sun, Ding Qiang, Scorilas Andreas, Lin Sicheng, Khella Heba Wz, Boulos Carl, Ibrahim Gena, Yousef George M
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada; Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada; Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Urol Oncol. 2019 Dec;37(12):955-963. doi: 10.1016/j.urolonc.2019.08.008. Epub 2019 Oct 19.
microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression by mRNA cleavage or translational repression. The miR-200 family is involved in the regulation of various tumor biologic processes including apoptosis, proliferation, invasion, and metastasis. They function mainly as tumor suppressors. In this study, we aim to validate the prognostic significance of miR-200 family using large cohort of primary clear cell renal cell carcinoma (ccRCC) and matched normal tissue and to explore the role of miR-200 family in RCC pathogenesis and progression.
We analyzed the expression of 3 members of the miR-200 family; miR-141, miR-200b, and miR-200c, between primary ccRCC, matched normal renal tissues, and nonmatched metastatic RCC. We compared clinicopathologic parameter including disease-free survival to miR-200 family expression. Additionally, we validated our results using The Cancer Genome Atlas dataset. We explored functional role of these miRNAs by bioinformatics analyses.
Expression of miR-200 family significantly decreased in cancer compared to non-neoplastic tissues. miR-141 and miR-200b were significantly down-regulated in metastatic than primary tumors. There was statistically significant negative association between all 3 miRNAs and tumor size and stage. As binary variables, univariate analyses revealed that miR-141, miR-200b, and miR-200c-positive ccRCC patients have a statistically significant lower chance of disease-recurrence or relapse and multivariate analyses showed miR-200b and miR-200c-positive patients have longer disease-free survival. We could predict disease-free survival better when 2 or more miRNAs were used as a combination. Overall survival analysis using The Cancer Genome Atlas data revealed that miR-200b-positive patients have significantly better survival. These results suggest that miR-141, miR-200b, and miR-200c are independent prognostic markers for ccRCC. Targets of these miRNAs are associated with pathways related to cancer invasion and metastasis, including TRAIL pathway, VEGF and VEGFR signaling network, and epithelial-mesenchymal transition.
微小RNA（miRNA）是一类小的非编码RNA，通过mRNA切割或翻译抑制来调节基因表达。miR-200家族参与多种肿瘤生物学过程的调控，包括凋亡、增殖、侵袭和转移。它们主要发挥肿瘤抑制因子的作用。在本研究中，我们旨在利用大量原发性透明细胞肾细胞癌（ccRCC）及配对的正常组织队列验证miR-200家族的预后意义，并探讨miR-200家族在RCC发病机制和进展中的作用。
我们分析了miR-200家族的3个成员，即miR-141、miR-200b和miR-200c在原发性ccRCC、配对的正常肾组织以及非配对的转移性RCC中的表达情况。我们将包括无病生存期在内的临床病理参数与miR-200家族的表达进行了比较。此外，我们使用癌症基因组图谱数据集验证了我们的结果。我们通过生物信息学分析探索了这些miRNA的功能作用。
与非肿瘤组织相比，miR-200家族在癌症中的表达显著降低。与原发性肿瘤相比，miR-141和miR-200b在转移性肿瘤中显著下调。所有3种miRNA与肿瘤大小和分期之间存在统计学上的显著负相关。作为二元变量，单因素分析显示miR-141、miR-200b和miR-200c阳性的ccRCC患者疾病复发或复发的几率在统计学上显著较低，多因素分析显示miR-200b和miR-200c阳性的患者无病生存期更长。当将2种或更多种miRNA联合使用时，我们能更好地预测无病生存期。使用癌症基因组图谱数据进行的总生存期分析显示，miR-200b阳性的患者生存期显著更好。这些结果表明，miR-141、miR-200b和miR-200c是ccRCC的独立预后标志物。这些miRNA的靶标与癌症侵袭和转移相关的通路有关，包括TRAIL通路、VEGF和VEGFR信号网络以及上皮-间质转化。
