Cancer-derived exosome miRNAs induce skeletal muscle wasting by Bcl-2-mediated apoptosis in colon cancer cachexia.
Cancer-derived exosome miRNAs induce skeletal muscle wasting by Bcl-2-mediated apoptosis in colon cancer cachexia.
复制标题
癌症来源的外泌体 miRNA 通过 Bcl-2 介导的结肠癌恶病质细胞凋亡诱导骨骼肌消耗
DOI：
10.1016/j.omtn.2021.04.015
复制
发表时间：
2021-06-04
期刊：
影响因子：
--
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Miao C;Zhang W;Feng L;Gu X;Shen Q;Lu S;Fan M;Li Y;Guo X;Ma Y;Liu X;Wang H;Zhang X
癌症恶病质是一种全身代谢紊乱综合征，伴有严重的肌肉组织萎缩，其中可能涉及癌症外泌体。对临床样本的分析表明，血清外泌体浓度与癌症恶病质的发展相关。C26细胞分泌的Exosomes在体外可使C2 C12肌管直径减小，在体内可使小鼠肌力和胫骨前肌（TA）重量降低。GW 4869是一种外泌体排泄抑制剂，可改善C26荷瘤小鼠的肌肉萎缩。microRNA（miRNA）测序（miRNA-seq）分析表明，miR-195 a-5 p和miR-125 b-1- 3 p在C26外泌体中比在MC 38细胞（非恶病质）分泌的外泌体中更丰富。miR-195 a-5 p和miR-125 b-1- 3 p模拟物均可诱导C2 C12成肌细胞萎缩。在用miR-195 a-5 p和miR-125 b-1- 3 p模拟物转染的C2 C12成肌细胞中、在C26荷瘤小鼠的腓肠肌中以及在用C26外来体注射的TA肌肉中观察到Bcl-2的下调和凋亡信号通路的激活。双荧光素酶检测结果证实miR-195 a-5 p/miR-125 b-1- 3 p靶向Bcl-2。Bcl-2的过表达成功地逆转了由两种miRNA模拟物诱导的C2 C12成肌细胞的萎缩。这些结果表明，富含癌外泌体的miRNA可能通过靶向Bcl-2介导的细胞凋亡诱导肌肉萎缩。Zhang及其同事报道，C26 exosome/miR-125 b-1- 3 p/miR-195 a-5 p通过抑制靶基因bcl 2和癌症恶病质期间的凋亡途径介导骨骼肌萎缩。他们的工作表明，抑制C26 exosomes/miRNA和凋亡途径是一种对抗结肠癌恶病质诱导的肌肉萎缩的新方法。
Cancer cachexia is a kind of whole-body metabolic disorder syndrome accompanied by severe wasting of muscle tissue in which cancer exosomes may be involved. Analysis of clinical samples showed that the serum exosome concentrations were correlated with the development of cancer cachexia. Exosomes secreted by C26 cells could decrease the diameter of C2C12 myotubes in vitro and decrease mouse muscle strength and tibialis anterior (TA) muscle weight in vivo. GW4869, an inhibitor of exosome excretion, ameliorated muscle wasting in C26 tumor-bearing mice. MicroRNA (miRNA) sequencing (miRNA-seq) analysis suggested that miR-195a-5p and miR-125b-1-3p were richer in C26 exosomes than in exosomes secreted from MC38 cells (non-cachexic). Both miR-195a-5p and miR-125b-1-3p mimics could induce atrophy of C2C12 myoblasts. Downregulation of Bcl-2 and activation of the apoptotic signaling pathway were observed in C2C12 myoblasts transfected with miR-195a-5p and miR-125b-1-3p mimics, in the gastrocnemius muscle of C26 tumor-bearing mice and in the TA muscle injected with C26 exosomes. Results of dual-luciferase assay confirmed the targeting of miR-195a-5p/miR-125b-1-3p to Bcl-2. Overexpression of Bcl-2 successfully reversed atrophy of C2C12 myoblasts induced by the two miRNA mimics. These results suggested that cancer exosome enriched miRNAs might induce muscle atrophy by targeting Bcl-2-mediated apoptosis. Zhang and colleagues report that C26 exosome/miR-125b-1-3p/miR-195a-5p mediates skeletal muscle wasting via inhibition of the target gene bcl2 and the apoptosis pathway during cancer cachexia. Their work implies that inhibition of C26 exosomes/miRNA and the apoptosis pathway is a novel approach to counteract muscle wasting induced by colon cancer cachexia.
登录
查看更多内容
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
13.6
作者：
Conlan RS;Pisano S;Oliveira MI;Ferrari M;Mendes Pinto I
通讯作者：
Mendes Pinto I
影响因子：
5
作者：
Marinho R;Alcântara PSM;Ottoch JP;Seelaender M
通讯作者：
Seelaender M
影响因子：
8.9
作者：
von Haehling, Stephan;Anker, Stefan D.
通讯作者：
Anker, Stefan D.
影响因子：
81.5
作者：
Baracos, Vickie E.;Martin, Lisa;Fearon, Kenneth C. H.
通讯作者：
Fearon, Kenneth C. H.