Zhang Fang, Li Tiepeng, Han Lu, Qin Peng, Wu Zhao, Xu Benling, Gao Quanli, Song Yongping
The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014, Henan, PR China.
Department of Immunotherapy Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan, PR China.
Biochem Biophys Res Commun. 2018 Feb 19;496(4):1169-1175. doi: 10.1016/j.bbrc.2018.01.164. Epub 2018 Jan 31.
The existence of cancer stem cells within the tumor could lead to cancer therapy resistance. TGFβ1 is considered as one of the most powerful players in the generation of CSCs through induction of epithelial-mesenchymal transition in different types of cancer including lung cancer, however, the detailed mechanisms by which TGFβ1 contribute to EMT induction and CSC maintenance remains unclear. Here, we showed primary lung cancer cells treated by TGFβ1 exhibit mesenchymal features, including morphology and expression of mesenchymal marker in a time-dependent manner. We also observed long-term TGFβ1 exposure leads to an enrichment of a sub-population of CD44 CD90 cells which represent CSCs in lung cancer cells. Moreover, the differential expression microRNAs between CSCs and non-CSCs were identified using next-generation sequencing to screen key miRNAs which might contribute to TGFβ1-induced EMT and CSCs generation. Among those differentially expressed miRNAs, the expression of microRNA-138 was time-dependently down-regulated by TGFβ1 treatment. We further demonstrated primary lung cancer cells, in which we knockdown the expression of miR-138, exhibit mesenchymal phenotypes and stem cell properties. Taken together, these findings indicate TGFβ1-induced down-regulation of microRNA-138 contributes to EMT in primary lung cancer cells, and suggest that miR-138 might serve as a potential therapeutic target.
肿瘤内癌症干细胞的存在可能导致癌症治疗耐药性。转化生长因子β1（TGFβ1）被认为是通过诱导包括肺癌在内的不同类型癌症中的上皮-间质转化来产生癌症干细胞的最关键因素之一，然而，TGFβ1促进上皮-间质转化诱导和癌症干细胞维持的详细机制仍不清楚。在此，我们发现经TGFβ1处理的原发性肺癌细胞呈现间质特征，包括形态和间质标志物的表达呈时间依赖性。我们还观察到长期暴露于TGFβ1会导致CD44 CD90细胞亚群富集，这些细胞代表肺癌细胞中的癌症干细胞。此外，利用下一代测序鉴定癌症干细胞和非癌症干细胞之间差异表达的微小RNA，以筛选可能有助于TGFβ1诱导的上皮-间质转化和癌症干细胞生成的关键微小RNA。在这些差异表达的微小RNA中，微小RNA-138的表达在TGFβ1处理后呈时间依赖性下调。我们进一步证明，敲低miR-138表达的原发性肺癌细胞表现出间质表型和干细胞特性。综上所述，这些发现表明TGFβ1诱导的微小RNA-138下调有助于原发性肺癌细胞的上皮-间质转化，并提示miR-138可能作为一个潜在的治疗靶点。
