Mir-144-3p Promotes Cell Proliferation, Metastasis, Sunitinib Resistance in Clear Cell Renal Cell Carcinoma by Downregulating ARID1A
Mir-144-3p Promotes Cell Proliferation, Metastasis, Sunitinib Resistance in Clear Cell Renal Cell Carcinoma by Downregulating ARID1A
复制标题
Mir-144-3p 通过下调 ARID1A 促进透明细胞肾细胞癌的细胞增殖、转移和舒尼替尼耐药
DOI：
10.1159/000484395
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发表时间：
2017-01-01
影响因子：
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通讯作者：
Zhang, Xiaoping
中科院分区：
文献类型：
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作者：
Xiao, Wen;Lou, Ning;Zhang, Xiaoping
背景/目标：我们先前进行了microRNA（miRNA）微阵列以鉴定透明细胞肾细胞癌（ccRCC）组织样本和术前/术后血浆的有效指标，其中我们鉴定了miR-144- 3 p作为oncomiRNA。然而，miR-144- 3 p的分子机制仍不清楚。本研究旨在探讨miR-144- 3 p在肾细胞癌侵袭、迁移和舒尼替尼耐药中的作用及其机制。研究方法：采用功能获得和功能丧失方法研究miR-144- 3 p在体外对细胞增殖、周期分布、克隆形成、迁移、侵袭、化疗敏感性的影响。异种移植模型用于评估miR-144- 3 p过表达对肿瘤发生的影响。通过生物信息学分析和双荧光素酶报告基因分析，确定AT-rich interactive domain 1A（ARID 1A）为miR-144- 3 p的直接靶基因。采用定量RT-PCR、Western blotting和免疫组化（IHC）检测ARID 1A mRNA和蛋白表达水平。结果：我们发现miR-144- 3 p过表达增强了ccRCC细胞的增殖、克隆形成、迁移、侵袭和化疗耐药性。值得注意的是，miR-144- 3 p的肿瘤活性是通过抑制ARID 1A的表达来介导的。ARIDIA的下调可促进miR-144- 3 p在细胞增殖、转移和化疗耐药中的作用。结论：ARID 1A mRNA和蛋白水平在ccRCC和裸鼠中均降低，且与miR-144- 3 p呈负相关。结论：较高的miR-144- 3 p可能通过靶向ARID 1A增强ccRCC的恶性程度和对舒尼替尼的耐药性，该观察结果可能揭示ccRCC治疗的新策略。
Background/Aims: We previously performed microRNA (miRNA) microarray to identify effective indicators of clear cell renal cell carcinoma (ccRCC) tissue samples and preoperative/postoperative plasma in which we identified miR-144-3p as an oncomiRNA. However, the molecular mechanism of miR-144-3p remains unclear. This study aims to explore the roles of miR-144-3p in the invasion, migration and Sunitinib-resistance in ccRCC and to elucidate the underlying mechanisms. Methods: Gain and loss of function approaches were used to investigate the cell proliferation, cycle distribution, clonogenicity, migration, invasion, chemosensitivity of miR-144-3p in vitro. The xenograft model was used to assess the effects of miR-144-3p overexpression on tumorigenesis. Bioinformatics analysis and dual-luciferase reporter assay were used to indentify AT-rich interactive domain 1A (ARID1A) as a direct target gene of miR-144-3p. Quantitative RT-PCR, Western blotting, and immunohistochemical (IHC) staining were used to explore ARID1A expression level of the mRNA and protein. Results: We found that miR-144-3p overexpression enhanced cell proliferation, clonogenicity, migration, invasion, and chemoresistance in ccRCC cells. Notably, the oncotumor activities of miR-144-3p were mediated by repressing the expression of ARID1A. The downregulation of ARIDIA could promote the function of miR-144-3p in cell proliferation, metastasis and chemoresistance. Consistently, ARID1A mRNA and protein levels were decreased in ccRCC and in nude mice, and they negatively correlated with miR-144-3p. Conclusion: Higher miR-144-3p may enhance malignancy and resistance to Sunitinib in ccRCC by targeting ARID1A, the observations may uncover novel strategies of ccRCC treatment.