环状 RNA circ_0000190 通过调控 miR-767-5p/MAPK4 通路抑制多发性骨髓瘤的进展。
CircRNA circ_0000190 inhibits the progression of multiple myeloma through modulating miR-767-5p/MAPK4 pathway.
机构信息
Department of Hematology, The Third Affiliated Hospital of Sun-yat Sen University, 600 Tianhe Avenue, Guangzhou, 510630, People's Republic of China.
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou, 510630, People's Republic of China.
出版信息
J Exp Clin Cancer Res. 2019 Feb 6;38(1):54. doi: 10.1186/s13046-019-1071-9.
BACKGROUND
Multiple myeloma (MM) accounts for 10% of all hematological malignancies. Dysregulation of microRNAs (miRNAs) or long non-coding RNAs (lncRNAs) has important impacts on progression of MM. Circular RNAs (circRNAs) are correlated with malignancy in the modulation of tumor progression. This study aims to investigate the effect of circ_0000190 on regulating the progression of MM.
METHOD
Microscopic examination via single molecule fluorescent in situ hybridization indicates the location of circ_0000190. qRT-PCR and Western blot were used to evaluate the expression of RNAs and proteins. Potential target of circ_0000190 was searched as miRNA, and examined by luciferase reporter assay. A computational screen was also conducted to search the potential target of miRNA. In vitro cell viability, proliferation, apoptosis assays and flow cytometric were performed to assess the effects of circ_0000190 and its target on MM. Mice model of human MM was established with subcutaneous xenograft tumor, qRT-PCR and western blot were performed to detect the underlying mechanisms of circ_0000190 on MM.
RESULTS
Circ_0000190 was located in the cytoplasm, and down-regulated in both bone marrow tissue and peripheral blood, while the target of circ_0000190, miR-767-5p, was up-regulated, suggesting a negative correlation between them. The binding ability between circ_0000190 and miR-767-5p was confirmed by luciferase reporter assay. Moreover, circ_0000190 inhibited cell viability, proliferation and induced apoptosis of MM thus inhibiting cell progression, which is partially through the negative regulation of miR-767-5p. Mitogen-activated protein kinase 4 (MAPK4) is a direct target of miR-767-5p. In addition, over-expression of miR-767-5p promoted cell progression by directly targeting and regulating MAPK4. The MM model mice with administration of circ_0000190 suppressed tumor growth and progression.
CONCLUSION
Our results revealed that the ability of circ_0000190 to protect against MM was inherited through repression of miR-767-5p, and miR-767-5p might be a tumor drive through targeting MAPK4. Therefore, a novel role of circ_0000190 on regulating the progression of MM was found, and the clinical application of circRNAs might represent a strategy in MM.
背景
多发性骨髓瘤（MM）占所有血液恶性肿瘤的 10%。miRNAs（miRNAs）或长非编码 RNA（lncRNAs）的失调对 MM 的进展有重要影响。环状 RNA（circRNAs）在肿瘤进展的调节中与恶性肿瘤相关。本研究旨在探讨 circ_0000190 对调节 MM 进展的影响。
方法
通过单分子荧光原位杂交进行显微镜检查，指示 circ_0000190 的位置。使用 qRT-PCR 和 Western blot 评估 RNA 和蛋白质的表达。circ_0000190 的潜在靶标被搜索为 miRNA，并通过荧光素酶报告基因检测进行检查。还进行了计算筛选，以搜索 miRNA 的潜在靶标。进行体外细胞活力、增殖、凋亡测定和流式细胞术，以评估 circ_0000190 及其靶标对 MM 的影响。通过皮下异种移植肿瘤建立人 MM 小鼠模型，进行 qRT-PCR 和 Western blot 检测，以研究 circ_0000190 对 MM 的潜在机制。
结果
circ_0000190 位于细胞质中，在骨髓组织和外周血中均下调，而 circ_0000190 的靶标 miR-767-5p 上调，表明它们之间存在负相关。荧光素酶报告基因检测证实了 circ_0000190 与 miR-767-5p 之间的结合能力。此外，circ_0000190 抑制 MM 的细胞活力、增殖并诱导细胞凋亡，从而抑制细胞进展，这部分是通过负调控 miR-767-5p 实现的。丝裂原活化蛋白激酶 4（MAPK4）是 miR-767-5p 的直接靶标。此外，过表达 miR-767-5p 通过直接靶向和调节 MAPK4 促进细胞进展。用 circ_0000190 处理的 MM 模型小鼠抑制肿瘤生长和进展。
结论
我们的研究结果表明，circ_0000190 通过抑制 miR-767-5p 来保护 MM 的能力是通过遗传的，而 miR-767-5p 可能通过靶向 MAPK4 成为肿瘤驱动因子。因此，发现了 circ_0000190 调节 MM 进展的新作用，circRNAs 的临床应用可能代表 MM 的一种策略。
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