miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis
miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis
复制标题
miR-28-5p-IL-34-巨噬细胞反馈环调节肝细胞癌转移
DOI：
10.1002/hep.28445
复制
发表时间：
2016-05-01
期刊：
影响因子：
13.5
通讯作者：
Zhou, Jian
中科院分区：
文献类型：
--
作者：
Zhou, Shao-Lai;Hu, Zhi-Qiang;Zhou, Jian
MicroRNAs （miRNAs）在肿瘤转移调控中起着至关重要的作用。然而，这些分子在肝细胞癌（HCC）中的作用尚未完全阐明。在本研究中，我们采用mirna测序方法，鉴定出22种参与HCC转移的mirna。其中一种miR-28-5p在hcc中下调。这种下调与肿瘤转移、复发和不良生存率相关。生物功能研究显示，miR-28-5p缺失促进了裸鼠的肿瘤生长和转移，但不改变HCC细胞的体外生物学特性。通过基因表达谱和生物信息学分析，我们发现白细胞介素-34 （IL-34）是miR-28-5p的直接靶点，miR-28-5p缺乏对HCC生长和转移的影响依赖于IL-34介导的肿瘤相关巨噬细胞（TAM）浸润。此外，我们发现miR-28-5p- il -34信号诱导的tam通过转化生长因子β 1抑制HCC细胞中miR-28-5p的表达，导致miR-28-5p- il -34巨噬细胞正反馈回路。在临床HCC样本中，miR-28-5p水平与IL-34表达和tam数量呈负相关。miR-28-5p低表达、IL-34水平高、tam数量多的患者预后较差，总生存期短，复发时间短。结论：mir -28-5p- il -34巨噬细胞反馈回路调节HCC转移，是一种新的预后因素，也是HCC的治疗靶点。(肝脏病学63:1560 2016;1575)
MicroRNAs (miRNAs) play a critical role in regulation of tumor metastasis. However, the role of these molecules in hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we employed miRNA-sequencing and identified 22 miRNAs involved in HCC metastasis. One of these, miR-28-5p, was down-regulated in HCCs. This down-regulation correlated with tumor metastasis, recurrence, and poor survival. Biofunctional investigations revealed that miR-28-5p deficiency promoted tumor growth and metastasis in nude mice without altering the in vitro biological characteristics of HCC cells. Through gene expression profiles and bioinformatics analysis, we identified interleukin-34 (IL-34) as a direct target of miR-28-5p, and the effects of miR-28-5p deficiency on HCC growth and metastasis was dependent on IL-34-mediated tumor-associated macrophage (TAM) infiltration. Moreover, we found that TAMs induced by miR-28-5p-IL-34 signaling inhibit miR-28-5p expression on HCC cells by transforming growth factor beta 1, resulting in an miR-28-5p-IL-34-macrophage-positive feedback loop. In clinical HCC samples, miR-28-5p levels were inversely correlated with IL-34 expression and the number of TAMs. Patients with low miR-28-5p expression, high IL-34 levels, and high numbers of TAMs had a poor prognosis with shorter overall survival and time to recurrence. Conclusion: A miR-28-5p-IL-34-macrophage feedback loop modulates HCC metastasis and serves as a novel prognostic factor as well as a therapeutic target for HCC. (Hepatology 2016;63:1560-1575)