Yang Xiaolin, Wang Baogang, Chen Wenbo, Man Xiaxia
Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin, 130021, PR China.
Department of Cardiac Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, PR China.
Exp Physiol. 2020 Aug;105(8):1360-1372. doi: 10.1113/EP088704. Epub 2020 Jul 8.
What is the central question of this study? The aim was to investigate the function of microRNA-188 in the biological characteristics of lung cancer stem cells and the molecular mechanisms involved. What is the main finding and its importance? This study highlights a new molecular mechanism involving microRNA-188, MDK and the Hippo signalling pathway that plays a suppressive role in biological activity of lung cancer stem cells. This finding might offer new insights into gene-based therapy for lung cancer.
MicroRNAs (miRNAs) have been implicated in lung cancer and reported as new promising diagnostic and therapeutic tools for cancer control. Here, we investigated the action of microRNA-188 (miR-188) in lung cancer stem cells. We first tested miR-188 expression in clinical samples of lung cancer patients, and a low expression profile of miR-188 was found. Next, we analysed the role of miR-188 in lung cancer stem cells with cell growth assays. To verify the in vitro results, we used a xenograft model to validate the capability of miR-188 in tumorigenesis. Overexpression of miR-188 reduced viability and metastasis of cancer stem cells. Similar results were reproduced in vivo, where overexpression of miR-188 retarded tumour growth in mice. We also identified MDK as a target of miR-188, and overexpression of MDK was found in lung cancer samples. Overexpressed MDK promoted the malignant behaviours of lung cancer stem cells. In addition, the Hippo pathway was found to be inactivated in lung cancer tissues, presenting as increased levels of YAP and TAZ. Suppression of the Hippo pathway also enhanced lung cancer stem cell activity and promoted the growth of xenograft tumours. To sum up, our results reveal that miR-188 inhibits the malignant behaviours of lung cancer stem cells and the growth of xenograft tumours. This study might offer new insights into gene-based therapies for cancer.
本研究的核心问题是什么？目的是研究微小RNA-188在肺癌干细胞生物学特性中的作用及其涉及的分子机制。主要发现及其重要性是什么？本研究突出了一种涉及微小RNA-188、Midkine（MDK）和Hippo信号通路的新分子机制，该机制在肺癌干细胞的生物学活性中起抑制作用。这一发现可能为肺癌的基因治疗提供新的见解。
微小RNA（miRNA）与肺癌有关，并且被报道为癌症控制中新的有前景的诊断和治疗工具。在此，我们研究了微小RNA-188（miR-188）在肺癌干细胞中的作用。我们首先检测了肺癌患者临床样本中miR-188的表达，发现其表达水平较低。接下来，我们通过细胞生长试验分析了miR-188在肺癌干细胞中的作用。为了验证体外实验结果，我们使用异种移植模型来验证miR-188的肿瘤发生能力。miR-188的过表达降低了癌症干细胞的活力和转移能力。在体内也得到了类似结果，miR-188的过表达抑制了小鼠肿瘤的生长。我们还确定MDK是miR-188的一个靶点，并且在肺癌样本中发现MDK过表达。过表达的MDK促进了肺癌干细胞的恶性行为。此外，发现Hippo通路在肺癌组织中失活，表现为Yes相关蛋白（YAP）和转录共激活因子（TAZ）水平升高。Hippo通路的抑制也增强了肺癌干细胞活性并促进了异种移植肿瘤的生长。总之，我们的结果表明miR-188抑制肺癌干细胞的恶性行为和异种移植肿瘤的生长。本研究可能为癌症的基因治疗提供新的见解。
