The Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
PLoS One. 2013 Aug 12;8(8):e70427. doi: 10.1371/journal.pone.0070427. eCollection 2013.
Recent studies have revealed that differentiated epithelial cells would acquire stem cell-like and tumorigenic properties following an Epithelial-Mesenchymal Transition (EMT). However, the signaling pathways that participate in this novel mechanism of tumorigenesis have not been fully characterized. In Runx3 (-/-) p53 (-/-) murine gastric epithelial (GIF-14) cells, EMT-induced plasticity is reflected in the expression of the embryonal proto-oncogene Hmga2 and Lgr5, an exclusive gastrointestinal stem cell marker. Here, we report the concurrent activation of an EGFR/Ras gene expression signature during TGF-β1-induced EMT in GIF-14 cells. Amongst the altered genes was the induction of Egfr, which corresponded with a delayed sensitization to EGF treatment in GIF-14. Co-treatment with TGF-β1 and EGF or the expression of exogenous KRas led to increased Hmga2 or Lgr5 expression, sphere initiation and colony formation in soft agar assay. Interestingly, the gain in cellular plasticity/tumorigenicity was not accompanied by increased EMT. This uncoupling of EMT and the induction of plasticity reveals an involvement of distinct signaling cues, whereby the EGFR/Ras pathway specifically promotes stemness and tumorigenicity in EMT-altered GIF-14 cells. These data show that the EGFR/Ras pathway requisite for the sustenance of gastric stem cells in vivo and in vitro is involved in the genesis and promotion of EMT-induced tumor-initiating cells.
最近的研究表明，上皮细胞在经历上皮-间充质转化（EMT）后会获得类似干细胞和致瘤的特性。然而，参与这种新的肿瘤发生机制的信号通路尚未完全阐明。在 Runx3(-/-)p53(-/-)鼠胃上皮（GIF-14）细胞中，EMT 诱导的可塑性反映在胚胎原癌基因 Hmga2 和 Lgr5 的表达上，Lgr5 是胃肠道干细胞的特异性标记。在这里，我们报告了在 TGF-β1 诱导的 GIF-14 细胞 EMT 过程中 EGFR/Ras 基因表达谱的同时激活。在改变的基因中，Egfr 的诱导与 GIF-14 对 EGF 治疗的敏感性延迟有关。TGF-β1 和 EGF 的共同处理或外源性 KRas 的表达导致 Hmga2 或 Lgr5 表达增加、球体起始和软琼脂试验中的集落形成。有趣的是，细胞可塑性/致瘤性的增加并没有伴随着 EMT 的增加。这种 EMT 的去耦联和可塑性的诱导揭示了不同信号通路的参与，其中 EGFR/Ras 途径特异性地促进 EMT 改变的 GIF-14 细胞中的干性和致瘤性。这些数据表明，体内和体外维持胃干细胞所需的 EGFR/Ras 途径参与了 EMT 诱导的肿瘤起始细胞的发生和促进。
