Abstract
Wnt and Notch signaling pathways both play essential roles and interact closely in development and carcinogenesis, but their interaction in non-small-cell lung cancer (NSCLC) is poorly unknown. Here we investigated the effects of CHIR99021, a Wnt signaling agonist, or Notch3-shRNA, or the combined application of CHIR99021 and Notch3-shRNA on cell proliferation and apoptosis, as well as the expressions of Notch3, its downstream genes, cyclinA and caspase-3. Our results showed that CHIR99021 up-regulated the expression of Notch3 protein and HES1 and HEYL mRNA. CHIR99021 promoted cell proliferation and the expression of cyclinA, which were inhibited by Notch3-shRNA in these three cell lines. Moreover, Notch3-shRNA significantly attenuated the positive effects of CHIR99021 on cell proliferation and cyclinA in H460 and H157. As for apoptosis, Notch3-shRNA induced cell apoptosis and increased the expression of caspase-3, whereas CHIR99021 showed the different effects in these three cell lines. The inhibitory effect of CHIR99021 on apoptosis was significantly weakened by Notch3-shRNA only in H460. Overall, although the effects of CHIR99021 and the combined application of CHIR99021 and Notch3-shRNA on the cell proliferation and apoptosis aren’t completely similar in the three cell lines, our findings still indicate that Notch3 signaling can be activated by canonical Wnt signaling and a functional link between Wnt and Notch signaling pathways exists in NSCLC, at least, which partially is associated with their regulations on the expressions of cyclinA and caspase-3.
Highlights
Notch and Wnt signaling pathways are both high-conserved pathways in the development of invertebrate and vertebrate, which participate in a variety of cell biological properties including cell polarity, proliferation, differentiation, and migration
We found that lithium chloride (LiCl), which inhibited glycogen synthase kinase 3β (GSK-3β) activity in vivo and vitro, and mimicked the biochemical effect of Wnt signaling by leading to stabilization of β-catenin protein, upregulated Notch3 signaling, and Notch3 siRNA weakened the effects of LiCl on the cell cycle of Non-small-cell lung cancer (NSCLC) cell lines [14]
To further elucidate whether a functional cross talk exists between the two pathways in NSCLC, we examined the impact of CHIR99021, a Wnt signaling agonist, or Notch3-short hairpin RNA (shRNA), or the combined application of CHIR99021 and Notch3-shRNA on cell proliferation and apoptosis
Summary
Notch and Wnt signaling pathways are both high-conserved pathways in the development of invertebrate and vertebrate, which participate in a variety of cell biological properties including cell polarity, proliferation, differentiation, and migration. The aberrant activation of these pathways plays an important role in tumor development and progression. NSCLC appears to actively utilize the above conserved developmental pathways. Both down-regulations of the Wnt antagonists and up-regulations of the key Wnt components have been observed in NSCLC tissues, and are associated with a poor prognosis and recurrence [3,4,5,6]. Previous studies concerned with the pathogenesis of lung cancer have identified that Notch played an essential role in NSCLC [9,10,11,12,13]. Regarding to the cross talk between the two signaling pathways in NSCLC, the data are not much
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