MiR-4319 induced an inhibition of epithelial-mesenchymal transition and prevented cancer stemness of HCC through targeting FOXQ1
MiR-4319 induced an inhibition of epithelial-mesenchymal transition and prevented cancer stemness of HCC through targeting FOXQ1
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MiR-4319 通过靶向 FOXQ1 诱导上皮间质转化的抑制并预防 HCC 的癌症干细胞
DOI：
10.7150/ijbs.38000
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发表时间：
2019-01-01
影响因子：
9.2
通讯作者：
Liu, Qingguang
中科院分区：
文献类型：
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作者：
Han, Shaoshan;Shi, Yu;Liu, Qingguang
肿瘤中存在的异质性是治疗反应差的原因。因此，阐明肝细胞癌瘤内异质性的分子机制对于发现新的治疗方法以改善患者预后具有重要意义。值得注意的是，肝细胞癌中存在的肿瘤干细胞(CSCs)可以解释异质性和复发性的病理特征。越来越多的研究证实，表达异常的microRNAs(MiRNAs)参与了肝癌的发生和发展。然而，目前关于肝癌中特定的miR-4319的信息很少。在此，我们证明了miR-4319在肝癌标本和细胞中的表达水平显著低于正常肝组织，并且miR-4319在肿瘤标本中的表达下调与肿瘤的大小、组织学分级和静脉侵犯有关。通过一系列的功能实验，我们证明miR-4319通过靶向FOXQ1(Forkhead Box Q1)抑制肝癌细胞的增殖，促进细胞凋亡，抑制上皮-间充质转化(EMT)，防止肿瘤干细胞分化。体内肿瘤发生实验发现，与对照组相比，缺失miR-4319可促进肿瘤生长，并上调EMT和CSC标记物的表达。FOXQ1表达的恢复也部分逆转了miR-4319对肝癌细胞的生物学效应。因此，miR-4319作为一种转录后调控因子，在抑制肝癌的恶性进展中发挥着重要作用，我们的研究强调miR-4319/FOXQ1级联序列是一个潜在的征服肝癌的治疗靶点。
The heterogeneity existing in tumours is responsible for the poor response to treatment. Therefore, elucidating the molecular mechanisms of intratumoural heterogeneity in hepatocellular carcinoma (HCC) is vital for the discovery of new therapeutic methods for improving the prognosis of patients. Of note, cancer stem cells (CSCs) existing in HCC may explain the pathological properties of heterogeneity and recurrence. An increasing number of studies have confirmed that abnormally expressed microRNAs (miRNAs) take part in the carcinogenesis as well as the aggravation of HCC. However, little information is currently available about the specific miR-4319 in HCC. Herein, we demonstrated that the level of miR-4319 was remarkably decreased in HCC specimens and cells compared to that in normal counterparts and that the depression of miR-4319 in tumour specimens correlates with tumour size, histological grade and venous invasion. Through a series of functional experiments, we illustrated that miR-4319 repressed cell proliferation, accelerated apoptosis, inhibited epithelial-mesenchymal transition (EMT) and prevented cancer stemness in HCC cells by targeting FOXQ1 (Forkhead box Q1). An in vivo tumourigenesis assay uncovered that depletion of miR-4319 in Hep3B cells increased tumour growth and elevated the expression of EMT and CSC markers in comparison to those of the control group. Restoration of FOXQ1 expression also partially reversed the miR-4319-induced biological effects on HCC cells. Thus, miR-4319, as a posttranscriptional regulator, plays a profound role in suppressing the malignant progression of HCC, and our study highlights the miR-4319/FOXQ1 cascade as a potential therapeutic target for conquering HCC.