来自复旦大学的研究人员证实一种名为MicroRNA-26a 的miRNA通过靶向IL-6-Stat3信号通路，参与了肝癌肿瘤生长和转移过程。相关研究论文已被在国际著名肝脏疾病杂志Hepatology（最新影响因子11.665）接受并在线发布。
复旦大学的钦伦秀（Lun-Xiu Qin）教授和董琼珠（Qiong-Zhu Dong）博士是这篇文章的共同通讯作者。钦伦秀教授是主要研究方向为肝癌转移复发的机理及其防治。现为973首席科学家、 “教育部肝癌转移机理与防治创新团队”带头人，迄今发表论文近100篇。
MicroRNA(miRNA)是近年来新发现的一类非编码单链小分子RNA，长约19-25个核苷酸(nucleotide，nt)，在转录后水平调控基因的表达，与动植物的组织器官发育、细胞分化和凋亡、胰岛素分泌、脂肪代谢等生命活动密切相关，其表达异常会导致肿瘤等重大疾病。目前已知多种miRNA与肿瘤的发生、分化程度、转移及预后密切相关。近来有研究发现miR-26a下调与癌症的不良预后存在关联，然而却并不清楚其分子功能机制。
在这项研究中，研究人员调查了miR-26a在肝癌肿瘤生长和转移中的作用，发现在肝癌组织中miR-26a往往下调，且与肝癌复发及转移存在相关性。通过功能获得性和功能缺失研究，研究人员证实miR-26a在体外显著抑制了细胞增殖、迁移和侵袭。此外，miR-26a诱导了肝癌细胞G1期阻滞，并促进了细胞凋亡。在负荷人类肝癌的裸鼠模型中，研究人员证实miR-26a抑制了肿瘤的生长与转移。
在进一步的机制研究中，研究人员将Interleukin-6 (IL-6)确定为miR-26a的靶点。他们证实在肝癌细胞中抑制IL-6可获得与miR-26a诱导相似的效应。相比之下，IL-6治疗可以消除miR-26a上调诱导的效应。此外，miR-26a显著抑制了Stat3靶基因如Bcl-2、Mcl-1、cyclin D1和MMP2的表达。IL-6治疗可以对抗这一效应。借助shIL-6抑制IL-6，研究人员发现其诱导了对p-Stat3和主要靶基因的表达抑制效应，与miR-26a诱导效应相似。在肝癌细胞中，IL-6的mRNA和蛋白质水平与miR-26a呈负相关。
此外，肝癌组织中高表达miR-26a或低表达IL-6的患者具有较好的预后，及更长的总生存期（OS）和复发时间(TTR)。多元分析结果表明，miR-26a、IL-6及组合是肝癌患者总生存期和复发时间的独立预后指标。
新研究结果表明，miR-26a可通过IL-6-Stat3信号通路来抑制肿瘤生长及转移，从而为肝癌提供了一个新的有潜力的预后标记及治疗靶点。(生物谷Bioon.com)
doi: 10.1002/hep.26305
PMC:
PMID:
MicroRNA-26a suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting IL-6-Stat3 pathway
Yang X, Liang L, Zhang XF, Jia HL, Qin Y, Zhu XC, Gao XM, Qiao P, Zheng Y, Sheng YY, Wei JW, Zhou HJ, Ren N, Ye QH, Dong QZ, Qin LX.
Down-regulation of miR-26a is found to be associated with poor prognosis of hepatocellular carcinoma (HCC), but its functional mechanism in HCC remains unclear. In this study, we investigated the roles of miR-26a in tumor growth and metastasis of HCC and found that miR-26a was frequently down-regulated in HCC tissues. Down-regulation of miR-26a correlated with HCC recurrence and metastasis. Through gain- and loss-of-function studies, miR-26a was demonstrated to significantly inhibit in vitro cell proliferation, migration, and invasion. In addition, miR-26a induced G1 arrest and promoted apoptosis of HCC cells. Importantly, miR-26a suppressed in vivo tumor growth and metastasis in nude mice models bearing human HCC. Interleukin-6 (IL-6) was identified as a target of miR-26a. Knockdown of IL-6 induced effects on HCC cells similar to those induced by miR-26a. In contrast, IL-6 treatment abrogated the effects induced by miR-26a up-regulation. Moreover, miR-26a dramatically suppressed expression of Stat3 target genes including Bcl-2, Mcl-1, cyclin D1, and MMP2. IL-6 treatment antagonized this effect, while knockdown of IL-6 by shIL-6 induced inhibitory effects on the expression of p-Stat3 and its main target genes, similar to miR-26a. The mRNA and protein levels of IL-6 inversely correlated with miR-26a in HCCs. Patients with high miR-26a or low IL-6 in HCC tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, IL-6, and their combination were demonstrated to be independent prognostic indicators for OS and TTR of HCC patients. Conclusion: miR-26a could suppress tumor growth and metastasis of HCC through IL-6-Stat3 signaling and is a novel prognostic marker and therapeutic target for HCC.
