Abstract
Previously, we demonstrated that Prx II is important for survival of the gefitinib-resistant A549 (A549/GR) cell line, an NSCLC cell line derived by repeated exposure to gefitinib. Therefore, in this study, we used A549/GR cells to investigate the role of Prx II in GR NSCLC stemness. Initially, to explore the stemness characteristics and investigate the association of Prx II with those stemness characteristics, we successfully isolated a stem cell-like population from A549/GR cells. A549/GR CD133+ cells possessed important cancer stemness characteristics, including the abilities to undergo metastasis, angiogenesis, self-renewal, and to express stemness genes and epithelial–mesenchymal transition (EMT) markers. However, those characteristics were abolished by knocking down Prx II expression. MicroRNA 122 (miR-122) targets Prx II in A549/GR cancer stem cells (CSCs), thereby inhibiting the stemness characteristics in vitro and in vivo. Next, we investigate whether miR-122 overexpression was associated with Prx II expression and Prx-II-induced stemness characteristics, we transfected miR-122 into A549/GR CSCs. MiR-122 inhibited A549/GR stemness by downregulating the Hedgehog, Notch, and Wnt/β-catenin pathways. Taken together, our data suggest that Prx II promotes A549/GR stemness, and that targeting Prx II and miR-122 is a potentially viable strategy for anti-cancer-stem cell therapy in GR NSCLCs.
Highlights
Peroxiredoxins (Prxs) comprise an important superfamily of cysteine (Cys)-based antioxidant enzymes, which are divided into three subclasses based on the number of conserved Cys residues participating in the redox reaction, i.e., the MicroRNA-122 negatively associates with peroxiredoxin-II expression in human gefitinib-resistant lung. . .cells (CSCs) are considered to be responsible for cancer progression, metastasis, and resistance to therapy [15]
Western blot analysis was performed to verify that Prx II was expressed in A549/GR cells and to observe Prx II expression in other GR non-small cell lung cancer (NSCLC) cells
Parallel experiments showed that higher expression of the cancer stem cells (CSCs) marker, CD133 was present in GR NSCLC cells, compared with MOCK cells (Fig. 1a)
Summary
Peroxiredoxins (Prxs) comprise an important superfamily of cysteine (Cys)-based antioxidant enzymes, which are divided into three subclasses based on the number of conserved Cys residues participating in the redox reaction, i.e., the MicroRNA-122 negatively associates with peroxiredoxin-II expression in human gefitinib-resistant lung. . .cells (CSCs) are considered to be responsible for cancer progression, metastasis, and resistance to therapy [15]. Recent studies have showed that miR-122 targets oncogenes, such as cyclin G1 and Bcl, thereby suppressing tumor proliferation [18, 19]. Apoptosis and cell cycle arrest can be induced by miR-122 overexpression in NSCLC cells [19, 20]. One study demonstrated that miR-122 targets Prx II in HCC. MiR-122 downregulates Prx II expression by binding to Prx II and inhibits HCC cell growth by inducing apoptosis [21]. We investigated the Prx II expression and mechanistic links that could explain the potential of Prx II in driving CSC properties, such as stemness, cell proliferation, metastasis, and angiogenesis in A549/GR stem cells. Our findings provide new insights into the miR-122mediated downregulation of A549/GR stem cell properties via Prx II inhibition
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