姜黄素对多发性骨髓瘤中 EZH2- miR-101 调节反馈环的作用及机制。
Effect and Mechanism of Curcumin on EZH2 - miR-101 Regulatory Feedback Loop in Multiple Myeloma.
机构信息
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
Department of pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
出版信息
Curr Pharm Des. 2018;24(5):564-575. doi: 10.2174/1381612823666170317164639.
BACKGROUND
Multiple myeloma is the second most prevalent hematologic malignancy and thought to be incurable. Therefore, it's urgent to find new drugs for treatment. Some experiments have shown that curcumin might have great potential in treating multiple myeloma, while the mechanism is still unknown. EZH2 and SUZ12 are the core proteins in PRC2 and their expressions are increased in various human cancers, including the poor prognostic multiple myeloma. Meanwhile, the regulation of miRNAs and EZH2 has been demonstrated in other cancer researches, like lung cancer, pancreatic cancer, leukemia and so on.
OBJECTIVE
To reveal the mechanism behind the anti-tumor effect of cucurmin in multiple myeloma.
METHOD
The effect of curcumin on the growth of MM cells was studied by MTT assay in the MM cell lines RPMI8226 and U266. Apoptosis was measured by Annexin V-FITC/PI double staining method. Western blotting, RT-PCR and luciferase activity assay were used to assess the expression of EZH2, SUZ12, miR-101 and downstream proteins such as E-cadherin, MMP9, c-Myc, cyclin D3, CDK4 and CDK6.
RESULTS
Curcumin could significantly inhibite the proliferation of MM cells in a time- and concentrationdependent manner. Curcumin induced apoptosis by inhibiting the expression of EZH2, and the apoptosis rates were 16.42% and 25.62% when the RPMI8226 cells incubated with 5 and 10 µmol/L of curcumin. For U266 cells, the apoptosis rates were 15.25% and 21.28%. The up-regulation of miR-101 led to the lower expression of EZH2. In adverse, the expression of EZH2 induced lower expression of miR-101. The down-stream proteins of miR-101 were regulated by curcumin and EZH2 at the same time.
CONCLUSION
Our experiments verified that the effect and mechanism of curcumin on multiple myeloma is via EZH2 - miR-101 regulatory feedback loop, which would lead us to a new way of investigating multiple myeloma and come up with new therapies in treating the disease.
背景
多发性骨髓瘤是第二大常见的血液系统恶性肿瘤，被认为是无法治愈的。因此，寻找新的治疗药物迫在眉睫。一些实验表明姜黄素在治疗多发性骨髓瘤方面可能具有巨大的潜力，但其机制尚不清楚。EZH2 和 SUZ12 是 PRC2 的核心蛋白，它们的表达在各种人类癌症中增加，包括预后不良的多发性骨髓瘤。同时，miRNA 和 EZH2 的调节在其他癌症研究中如肺癌、胰腺癌、白血病等已得到证实。
目的
揭示姜黄素在多发性骨髓瘤中抗肿瘤作用的机制。
方法
通过 MTT 法检测姜黄素对多发性骨髓瘤细胞系 RPMI8226 和 U266 生长的影响。通过 Annexin V-FITC/PI 双染色法检测细胞凋亡。采用 Western blot、RT-PCR 和荧光素酶活性测定法评估 EZH2、SUZ12、miR-101 及其下游蛋白如 E-钙黏蛋白、MMP9、c-Myc、细胞周期蛋白 D3、CDK4 和 CDK6 的表达。
结果
姜黄素能显著抑制多发性骨髓瘤细胞的增殖，呈时间和浓度依赖性。姜黄素通过抑制 EZH2 的表达诱导细胞凋亡，当 RPMI8226 细胞与 5 和 10 µmol/L 的姜黄素孵育时，凋亡率分别为 16.42%和 25.62%。对于 U266 细胞，凋亡率分别为 15.25%和 21.28%。miR-101 的上调导致 EZH2 的表达降低。相反，EZH2 的表达诱导 miR-101 的表达降低。miR-101 的下游蛋白同时受到姜黄素和 EZH2 的调节。
结论
本实验验证了姜黄素对多发性骨髓瘤的作用及其机制是通过 EZH2-miR-101 调节反馈环，这将为我们研究多发性骨髓瘤提供新的途径，并为治疗该疾病提供新的治疗方法。
Zotero 插件