來自天津醫(yī)科大學(xué)和中山大學(xué)癌癥中心的研究人員在新研究中揭示：一種名為MicroRNA-10a的miRNA通過調(diào)控EphA4受體介導(dǎo)的上皮間質(zhì)轉(zhuǎn)化和細胞粘附,，參與了肝癌細胞轉(zhuǎn)移過程,。相關(guān)論文發(fā)表在在國際著名肝臟疾病雜志Hepatology上（最新影響因子11.665）上。
天津醫(yī)科大學(xué)的湯華（Hua Tang）教授和中山大學(xué)的李升平(Shengping Li)副教授為論文的共同通訊作者,。前者主要從事小RNA對腫瘤細胞惡性形為及小RNA對病毒增殖的調(diào)控研究,。后者擅長肝膽腫瘤診治及外科介入治療，尤其是膽道及胰腺腫瘤的治療,。
肝癌是一種嚴重威脅人類健康的疾病,，病死率在惡性腫瘤中居第3位。其發(fā)病原因可能是乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）引起的肝炎,、肝硬化以及黃曲霉素,、化學(xué)致癌物等其他因素，發(fā)病機制目前尚不完全清楚,。
MicroRNAs (miRNAs)是近年來生命科學(xué)領(lǐng)域的一個新的熱點,。miRNA是一類廣泛存在的非編碼小RNA，以干擾mRNA翻譯的方式負向調(diào)控基因的表達,。研究發(fā)現(xiàn)miRNA調(diào)節(jié)人類高達60%的基因表達,，參與生命過程一系列的重要進程，包括早期發(fā)育以及細胞增殖,、分化,、凋亡、死亡和脂肪代謝,。miRNA還可能具有癌基因和抑癌基因的作用,，表現(xiàn)為不同類型的腫瘤有其特異性的miRNA表達譜。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)。
在這篇文章中,，研究人員發(fā)現(xiàn)miR-10a可在體外促進QGY-7703細胞和HepG2細胞轉(zhuǎn)移和侵襲,。然而在體內(nèi)實驗中，他們發(fā)現(xiàn)miR-10a則抑制了轉(zhuǎn)移,。實驗粘附實驗表明,，miR-10a抑制了肝癌細胞與細胞外基質(zhì)的粘附，從而為體內(nèi)動物實驗的結(jié)果提供了解釋,。隨后,，研究人員證實酪氨酸激酶受體EphA4是miR-10a的直接和功能性靶基因。抑制EphA4可以獲得與miR-10a抑制相似的效應(yīng),，在肝癌細胞中異位表達EphA4可恢復(fù)miR-10a對于遷移,、侵襲和粘附的影響,。在進一步的研究中，研究人員證實miR-10a和EphA4調(diào)控了上皮間質(zhì)轉(zhuǎn)化過程和β1-integrin信號途徑,，從而影響了細胞侵襲和粘附,。
這些研究結(jié)果表明miR-10a通過直接靶向EphA4，在肝癌細胞的轉(zhuǎn)移特性調(diào)控中發(fā)揮了重要的作用,，由此對肝癌的發(fā)病機制提出了新見解,。(生物谷Bioon.com)
DOI: 10.1002/hep.26071
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PMID:
MicroRNA-10a is involved in the metastatic process by regulating Eph tyrosine kinase receptor A4-Mediated epithelial-mesenchymal transition and adhesion in hepatoma cells
Yan Yan1, Yue-Chen Luo1,§, Hai-Ying Wan1,§, Jun Wang2, Pei-Pei Zhang1, Min Liu1, Xin Li1, Shengping Li2,¶,*, Hua Tang1,‖,*
MicroRNAs (miRNAs) have been reported to be associated with the development of cancers. However, the function of miRNAs in human hepatocellular carcinoma (HCC) remains largely undefined. Here we found that overexpression of miR-10a promoted the migration and invasion of QGY-7703 and HepG2 cells in vitro but suppressed metastasis in vivo. Cell adhesion assays showed that miR-10a suppressed HCC cell-matrix adhesion, which could explain the results of the in vivo animal experiments. The Eph tyrosine kinase receptor, EphA4, was identified as the direct and functional target gene of miR-10a. Knockdown of EphA4 phenocopied the effect of miR-10a and ectopic expression of EphA4 restored the effect of miR-10a on migration, invasion, and adhesion in HCC cells. We further demonstrated that miR-10a and EphA4 regulated the epithelial-mesenchymal transition process and the β1-integrin pathway to affect cell invasion and adhesion. Conclusion: Our findings highlight the importance of miR-10a in regulating the metastatic properties of HCC by directly targeting EphA4 and may provide new insights into the pathogenesis of HCC.
