來自復(fù)旦大學(xué)的研究人員證實一種名為MicroRNA-26a 的miRNA通過靶向IL-6-Stat3信號通路,，參與了肝癌腫瘤生長和轉(zhuǎn)移過程。相關(guān)研究論文已被在國際著名肝臟疾病雜志Hepatology（最新影響因子11.665）接受并在線發(fā)布,。
復(fù)旦大學(xué)的欽倫秀（Lun-Xiu Qin）教授和董瓊珠（Qiong-Zhu Dong）博士是這篇文章的共同通訊作者。欽倫秀教授是主要研究方向為肝癌轉(zhuǎn)移復(fù)發(fā)的機理及其防治?，F(xiàn)為973首席科學(xué)家,、 “教育部肝癌轉(zhuǎn)移機理與防治創(chuàng)新團(tuán)隊”帶頭人,，迄今發(fā)表論文近100篇。
MicroRNA(miRNA)是近年來新發(fā)現(xiàn)的一類非編碼單鏈小分子RNA,，長約19-25個核苷酸(nucleotide,，nt)，在轉(zhuǎn)錄后水平調(diào)控基因的表達(dá),，與動植物的組織器官發(fā)育,、細(xì)胞分化和凋亡、胰島素分泌,、脂肪代謝等生命活動密切相關(guān),，其表達(dá)異常會導(dǎo)致腫瘤等重大疾病。目前已知多種miRNA與腫瘤的發(fā)生,、分化程度,、轉(zhuǎn)移及預(yù)后密切相關(guān)。近來有研究發(fā)現(xiàn)miR-26a下調(diào)與癌癥的不良預(yù)后存在關(guān)聯(lián),，然而卻并不清楚其分子功能機制,。
在這項研究中，研究人員調(diào)查了miR-26a在肝癌腫瘤生長和轉(zhuǎn)移中的作用,，發(fā)現(xiàn)在肝癌組織中miR-26a往往下調(diào),，且與肝癌復(fù)發(fā)及轉(zhuǎn)移存在相關(guān)性。通過功能獲得性和功能缺失研究,，研究人員證實miR-26a在體外顯著抑制了細(xì)胞增殖,、遷移和侵襲。此外,，miR-26a誘導(dǎo)了肝癌細(xì)胞G1期阻滯,，并促進(jìn)了細(xì)胞凋亡。在負(fù)荷人類肝癌的裸鼠模型中,，研究人員證實miR-26a抑制了腫瘤的生長與轉(zhuǎn)移,。
在進(jìn)一步的機制研究中，研究人員將Interleukin-6 (IL-6)確定為miR-26a的靶點,。他們證實在肝癌細(xì)胞中抑制IL-6可獲得與miR-26a誘導(dǎo)相似的效應(yīng),。相比之下，IL-6治療可以消除miR-26a上調(diào)誘導(dǎo)的效應(yīng),。此外,，miR-26a顯著抑制了Stat3靶基因如Bcl-2、Mcl-1,、cyclin D1和MMP2的表達(dá),。IL-6治療可以對抗這一效應(yīng)。借助shIL-6抑制IL-6,，研究人員發(fā)現(xiàn)其誘導(dǎo)了對p-Stat3和主要靶基因的表達(dá)抑制效應(yīng),，與miR-26a誘導(dǎo)效應(yīng)相似,。在肝癌細(xì)胞中，IL-6的mRNA和蛋白質(zhì)水平與miR-26a呈負(fù)相關(guān),。
此外,，肝癌組織中高表達(dá)miR-26a或低表達(dá)IL-6的患者具有較好的預(yù)后，及更長的總生存期（OS）和復(fù)發(fā)時間(TTR),。多元分析結(jié)果表明,，miR-26a、IL-6及組合是肝癌患者總生存期和復(fù)發(fā)時間的獨立預(yù)后指標(biāo),。
新研究結(jié)果表明,，miR-26a可通過IL-6-Stat3信號通路來抑制腫瘤生長及轉(zhuǎn)移，從而為肝癌提供了一個新的有潛力的預(yù)后標(biāo)記及治療靶點,。(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.
