Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma
Targeting miR-21 decreases expression of multi-drug resistant genes and promotes chemosensitivity of renal carcinoma
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DOI：
10.1177/1010428317707372
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发表时间：
2017-07-17
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影响因子：
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通讯作者：
Perrais, Michael
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作者：
Gaudelot, Kelly;Gibier, Jean-Baptiste;Perrais, Michael
肾细胞癌是成人肾脏最常见的肿瘤，约占成人恶性肿瘤的3%，通常对常规治疗具有高度抵抗性。MicroRNA是一类小的非编码RNA，先前已显示其促进恶性肿瘤的发生和进展。在这项研究中，我们将注意力集中在miR-21上，这是一种在癌症中通常上调的已充分描述的oncomiR。使用99个原发性肾细胞癌样本的队列，我们发现癌组织中的miR-21表达高于邻近的非肿瘤组织，而在分期、分级和转移结局方面没有观察到显著差异。在体外，miR-21在肾癌细胞系中也过表达，与HK-2人近端小管上皮细胞系相比。此外，使用Boyden小室和蛋白质印迹技术，我们还发现miR-21过表达增加了迁移、侵袭、增殖和抗凋亡信号通路，而使用基于抗miR-21的沉默策略观察到相反的结果。最后，我们评估了miR-21在介导肾细胞癌化疗耐药性中的作用，并进一步表明miR-21沉默显著（1）增加紫杉醇、5-氟尿嘧啶、奥沙利铂和多韦替尼的化疗敏感性;（2）降低多药耐药基因的表达;（4）增加SLC 22 A1/OCT 1、SLC 22 A2/OCT 2和SLC 31 A1/CTR 1铂内流转运蛋白的表达。总之，我们的研究结果表明，miR-21是肾癌进展的关键因素，并在化疗药物耐药性中发挥重要作用。在肾细胞癌中，靶向miR-21是一种潜在的新治疗策略，可改善化疗疗效，从而改善患者结局。
Renal cell carcinoma, the most common neoplasm of adult kidney, accounts for about 3% of adult malignancies and is usually highly resistant to conventional therapy. MicroRNAs are a class of small non-coding RNAs, which have been previously shown to promote malignant initiation and progression. In this study, we focused our attention on miR-21, a well described oncomiR commonly upregulated in cancer. Using a cohort of 99 primary renal cell carcinoma samples, we showed that miR-21 expression in cancer tissues was higher than in adjacent non-tumor tissues whereas no significant difference was observed with stages, grades, and metastatic outcome. In vitro, miR-21 was also overexpressed in renal carcinoma cell lines compared to HK-2 human proximal tubule epithelial cell line. Moreover, using Boyden chambers and western blot techniques, we also showed that miR-21 overexpression increased migratory, invasive, proliferative, and anti-apoptotic signaling pathways whereas opposite results were observed using an anti-miR-21-based silencing strategy. Finally, we assessed the role of miR-21 in mediating renal cell carcinoma chemoresistance and further showed that miR-21 silencing significantly (1) increased chemosensitivity of paclitaxel, 5-fluorouracil, oxaliplatin, and dovitinib; (2) decreased expression of multi-drug resistance genes; and (4) increased SLC22A1/OCT1, SLC22A2/OCT2, and SLC31A1/CTR1 platinum influx transporter expression. In conclusion, our results showed that miR-21 is a key actor of renal cancer progression and plays an important role in the resistance to chemotherapeutic drugs. In renal cell carcinoma, targeting miR-21 is a potential new therapeutic strategy to improve chemotherapy efficacy and consequently patient outcome.