MicroRNAs miR-125b and miR-100 suppress metastasis of hepatocellular carcinoma by disrupting the formation of vessels that encapsulate tumour clusters

小RNA 转移 癌症研究 肝细胞癌 PI3K/AKT/mTOR通路 细胞培养 生物 体内 化学 癌症 细胞生物学 信号转导 基因 遗传学 生物化学 生物技术
作者
Hui-Chao Zhou,Jian‐Hong Fang,Li-Ru Shang,Jun Zhang,Ye Sang,Li Xu,Yunfei Yuan,Min-Shan Chen,Limin Zheng,Yaojun Zhang,Shi‐Mei Zhuang
标识
DOI:10.1002/path.4804
摘要

We have previously shown that vessels that encapsulated tumour cluster (VETC), a prevalent vascular pattern in hepatocellular carcinoma (HCC), facilitates the entry of the whole tumour cluster into the bloodstream in an invasion-independent manner, and that angiopoietin 2 (Angpt2), the levels of which are increased in HCC cells, is essential for VETC formation. However, the mechanisms underlying VETC formation remains unclear. Herein, we characterized miR-125b and miR-100 as novel VETC suppressors by using human HCC specimens, and cell and animal models. We showed that reduced expression of either miR-125b or miR-100 in human HCC tissues was significantly associated with the presence of VETC, venous invasion of tumour cells, and the occurrence of endothelium-coated microemboli. To confirm the role of miR-125b and miR-100 in VETC formation and HCC metastasis, cell lines with stable miR-125b and miR-100 expression were established by using human VETC-2 cells and mouse Hepa1-6 cells, the hepatoma cells that developed xenografts with VETC patterns. Our results showed that expression of miR-125b or miR-100 in VETC-2 and Hepa1-6 cells dramatically reduced VETC formation in xenografts, and consequently inhibited in vivo metastasis, suggesting that miR-125b and miR-100 may attenuate metastasis by repressing VETC formation. Further investigation revealed that miR-125b directly suppressed the expression of Angpt2 by binding to its 3′-untranslated region, whereas miR-100 reduced the protein level of Angpt2 by targeting mechanistic target of rapamycin (MTOR) and blocking the MTOR–p70S6K signalling pathway. Moreover, the suppressive effect of miR-125b and miR-100 on VETC formation was abrogated by injecting Angpt2-expressing viruses into xenografts. Taken together, our findings imply that miR-125b and miR-100 negatively regulate Angpt2 expression through different mechanisms, in turn inhibit VETC formation, and consequently abrogate the VETC-dependent metastasis of hepatoma cells. This study uncovers new regulatory mechanisms of VETC formation, identifies novel functions of miR-125b and miR-100, and provides new targets for antimetastasis therapy of HCC. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
Akim应助xiaolaoshuboshi采纳,获得10
4秒前
Xutz应助落寞的玉兰采纳,获得10
4秒前
linxiangFYYY完成签到,获得积分10
4秒前
奋斗皮卡丘完成签到,获得积分10
6秒前
6秒前
SS发布了新的文献求助30
7秒前
8秒前
9秒前
9秒前
zby完成签到,获得积分10
10秒前
风雨晴鸿完成签到 ,获得积分10
10秒前
轻松小之发布了新的文献求助10
12秒前
科研通AI2S应助追寻锦程采纳,获得10
13秒前
13秒前
111发布了新的文献求助10
13秒前
tuao234举报求助违规成功
14秒前
井野浮举报求助违规成功
15秒前
kongxiangjiu举报求助违规成功
15秒前
15秒前
我来也发布了新的文献求助10
15秒前
16秒前
人参完成签到,获得积分10
16秒前
希望天下0贩的0应助yyyq0721采纳,获得10
19秒前
lull完成签到,获得积分10
19秒前
Bran发布了新的文献求助10
20秒前
课呢完成签到,获得积分10
22秒前
可爱的函函应助面圈采纳,获得10
22秒前
23秒前
人参发布了新的文献求助10
23秒前
mucheng完成签到,获得积分10
23秒前
24秒前
李大仁发布了新的文献求助10
24秒前
25秒前
我是老大应助111采纳,获得10
25秒前
26秒前
27秒前
28秒前
29秒前
SXYYXS发布了新的文献求助10
30秒前
31秒前
高分求助中
歯科矯正学 第7版(或第5版) 1004
SIS-ISO/IEC TS 27100:2024 Information technology — Cybersecurity — Overview and concepts (ISO/IEC TS 27100:2020, IDT)(Swedish Standard) 1000
Smart but Scattered: The Revolutionary Executive Skills Approach to Helping Kids Reach Their Potential (第二版) 1000
Semiconductor Process Reliability in Practice 720
GROUP-THEORY AND POLARIZATION ALGEBRA 500
Mesopotamian divination texts : conversing with the gods : sources from the first millennium BCE 500
Days of Transition. The Parsi Death Rituals(2011) 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3233196
求助须知:如何正确求助?哪些是违规求助? 2879802
关于积分的说明 8212752
捐赠科研通 2547256
什么是DOI,文献DOI怎么找? 1376718
科研通“疑难数据库(出版商)”最低求助积分说明 647682
邀请新用户注册赠送积分活动 623086