Deficiency of mitophagy receptor FUNDC1 impairs mitochondrial quality and aggravates dietary-induced obesity and metabolic syndrome
Deficiency of mitophagy receptor FUNDC1 impairs mitochondrial quality and aggravates dietary-induced obesity and metabolic syndrome
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MIR145-3p 通过靶向 HDAC4 促进自噬并增强多发性骨髓瘤中的硼替佐米敏感性
DOI：
10.1080/15548627.2019.1635380
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发表时间：
2019-04-08
期刊：
影响因子：
13.3
通讯作者：
Chen, Quan
中科院分区：
文献类型：
--
作者：
Wu, Hao;Wang, You;Chen, Quan
摘要多发性骨髓瘤（MM）是一种无法治愈的浆细胞恶性肿瘤，生存率低。自噬是一种由溶酶体活性介导的应激反应性分解代谢过程，在MM的病理生理学中起着至关重要的作用。越来越多的证据表明，失调的microRNAs（miRNAs）与多种人类癌症中的异常自噬相关。然而，迄今为止，很少有miRNA被报道直接调节MM病理生物学中的自噬。在这项研究中，我们研究了MIR 145 - 3 p（microRNA 145- 3 p）在MM中的作用，重点是细胞过程自噬和细胞死亡。我们的研究结果提供了证据表明MIR 145 - 3 p表达的下调与人类MM中的疾病进展相关。MIR 145 - 3 p通过直接靶向MM细胞中的HDAC 4（组蛋白脱乙酰酶4）触发自噬流，导致细胞凋亡增强。沉默HDAC 4重现了MIR 145 - 3 p的作用，而HDAC 4的增强表达消除了MIR 145 - 3 p的作用。此外，我们发现MIR 145 - 3 p对HDAC 4的抑制导致促凋亡蛋白BCL 2L 11的上调并导致MTORC 1失活，这反过来又导致增强的自噬和细胞死亡。重要的是，我们证明了MIR 145 - 3 p模拟物可以在体外和体内实验中增强硼替佐米的抗MM活性。总体而言，我们的研究结果表明，MIR 145 - 3 p通过诱导自噬细胞死亡在MM中发挥肿瘤抑制功能，并表明基于MIR 145 - 3 p的靶向治疗将代表MM治疗的新策略。缩略语：3-甲基丙烯酸：3-甲基腺嘌呤; 3个UTR：3.非翻译区; 7-AAD：7-氨基放线菌素D;会计师事务所：肌动蛋白β; ANXA 5：膜联蛋白A5; ATG5：自噬相关5例; ATG7：自噬相关7例; B2M：β 2-微球蛋白; BAF：巴弗洛霉素A1;第十一章：BCL 2样11例;波特：硼替佐米; CASP3：胱天蛋白酶3;胆囊收缩素-8：细胞计数试剂盒-8; CQ：氯喹; Ct：阈值循环;客户：对照组; DAPI：4 β，6-二脒基-2-苯基吲哚; GAPDH：甘油醛-3-磷酸脱氢酶; GFP：绿色荧光蛋白; HDAC 4：组蛋白脱乙酰酶4; ISS：国际分期系统; MAP 1 LC 3 B：微管相关蛋白1轻链3 β; miRNA：microRNA; MIR 145 - 3 p：microRNA 145 - 3 p; MM：多发性骨髓瘤; mRNA：信使RNA; MTOR：雷帕霉素激酶的机制靶点; MTOR 1：雷帕霉素激酶复合物1的机制靶标; PC：浆细胞; PFS：无进展生存期; qRT-PCR：定量逆转录PCR; RPS 6 KB 1：核糖体蛋白S6激酶B1; SD：标准差; siRNA：小干扰RNA; SQSTM 1：隔离体1; STV：饥饿; TUBB：微管蛋白β I类。
ABSTRACT Multiple myeloma (MM) is an incurable plasma cell malignancy with poor survival. Autophagy, a stress-responsive catabolic process mediated by lysosomal activity, plays a crucial role in the pathophysiology of MM. Growing evidence has indicated that dysregulated microRNAs (miRNAs) are associated with the aberrant autophagy in various human cancers. However, to date, few miRNAs have been reported to directly modulate autophagy in the pathobiology of MM. In this study, we investigated the role of MIR145-3p (microRNA 145-3p) in MM, with focus on cellular processes autophagy and cell death. Our results provided evidence that downregulation of MIR145-3p expression was associated with disease progression in human MM. MIR145-3p triggered autophagic flux through direct targeting of HDAC4 (histone deacetylase 4) in MM cells, leading to enhanced apoptosis. Silencing HDAC4 recapitulated the effects of MIR145-3p, whereas enforced expression of HDAC4 abrogated the effects of MIR145-3p. Furthermore, we showed that suppression of HDAC4 by MIR145-3p resulted in upregulation of the pro-apoptotic protein BCL2L11 and caused MTORC1 inactivation, which in turn led to enhanced autophagy and cell death. Importantly, we demonstrated that MIR145-3p mimic could potentiate the anti-MM activity of bortezomib in both in vitro and in vivo experiments. Overall, our findings indicate that MIR145-3p exerted a tumor suppression function in MM by inducing autophagic cell death and suggest that MIR145-3p-based targeted therapy would represent a novel strategy for MM treatment. Abbreviations: 3-MA: 3-methyladenine; 3ʹ-UTR: 3ʹ-untranslated region; 7-AAD: 7-aminoactinomycin D; ACTB: actin beta; ANXA5: annexin A5; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; BAF: bafilomycin A1; BCL2L11: BCL2 like 11; Bort: bortezomib; CASP3: caspase 3; CCK-8: Cell Counting Kit-8; CQ: chloroquine; Ct: threshold cycle; ctrl: control; DAPI: 4ʹ,6-diamidino-2-phenylindole; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HDAC4: histone deacetylase 4; ISS: International Staging System; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; miRNAs: microRNAs; MIR145-3p: microRNA 145-3p; MM: multiple myeloma; mRNA: messenger RNA; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PCs: plasma cells; PFS: progression-free survival; qRT-PCR: quantitative reverse transcription PCR; RPS6KB1: ribosomal protein S6 kinase B1; SD: standard deviation; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STV: starvation; TUBB: tubulin beta class I.