Cancer stem cells (CSCs) play significant roles in tumor initiation. MicroRNA-135a (miR-135a) induced the formation of a CD133+ subpopulation from a human papillomavirus-immortalized cervical epithelial cell line. Compared with the CD133- cells, the CD133+ cells expressed higher levels of miR-135a and OCT4, exhibited significantly higher tumorsphere forming capacity and the time required for tumorsphere formation was shortened in the second generation. Serum induction suppressed the expression of CD133, OCT4 and miR-135a, but increased expression of involucrin in the miR-135a-induced CD133+ cells. The miR-135a-induced CD133+ cells were tumorigenic in a limiting dilution approach in vivo. The cells expressed significantly higher level of active β-catenin and OCT4 than the CD133- counterpart. Wnt3a enhanced the expression of OCT4 and CD133 in cervical cancer cells but failed to enhance CD133 transcription in normal cervical cells. Wnt3a stimulation also increased tumorsphere size and self-renewal of miR-135a-induced CD133+ subpopulation. Wnt/β-catenin inhibition suppressed tumorsphere formation while Wnt3a partially nullified the inhibitory effect. Taken together, miR-135a induced the formation of a subpopulation of cells with CSC properties both in vitro and in vivo and the Wnt/β-catenin signaling pathway is essential to maintain its tumorigenicity.

中文翻译：

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MicroRNA-135a诱导的具有宫颈癌干细胞特性的CD133 +亚群形成。

癌症干细胞（CSC）在肿瘤发生中起重要作用。MicroRNA-135a（miR-135a）诱导了人类乳头瘤病毒永生化宫颈上皮细胞系CD133 +亚群的形成。与CD133-细胞相比，CD133 +细胞表达更高水平的miR-135a和OCT4，表现出明显更高的肿瘤球形成能力，第二代肿瘤球形成所需的时间缩短了。血清诱导抑制了CD133，OCT4和miR-135a的表达，但在miR-135a诱导的CD133 +细胞中总蛋白表达增加。miR-135a诱导的CD133 +细胞在体内有限稀释法中具有致瘤性。该细胞表达的活性β-catenin和OCT4水平明显高于CD133-对应物。Wnt3a增强了宫颈癌细胞中OCT4和CD133的表达，但未能增强正常宫颈细胞中CD133的转录。Wnt3a刺激还增加了肿瘤球大小和miR-135a诱导的CD133 +亚群的自我更新。Wnt /β-catenin抑制抑制了肿瘤球的形成，而Wnt3a部分抵消了抑制作用。两者合计，miR-135a在体外和体内均诱导具有CSC特性的细胞亚群的形成，而Wnt /β-catenin信号通路对于维持其致瘤性至关重要。Wnt /β-catenin抑制抑制了肿瘤球的形成，而Wnt3a部分抵消了抑制作用。两者合计，miR-135a在体外和体内均诱导具有CSC特性的细胞亚群的形成，而Wnt /β-catenin信号通路对于维持其致瘤性至关重要。Wnt /β-catenin抑制抑制了肿瘤球的形成，而Wnt3a部分抵消了抑制作用。两者合计，miR-135a在体外和体内均诱导具有CSC特性的细胞亚群的形成，而Wnt /β-catenin信号通路对于维持其致瘤性至关重要。