DDX5 promotes proliferation and tumorigenesis of non‐small‐cell lung cancer cells by activating β‐catenin signaling pathway

Abstract

The DEAD-box-protein DDX5 is an ATP-dependent RNA helicase that is frequently overexpressed in various cancers and acts as a transcriptional co-activator of several transcription factors, including β-catenin. DDX5 is reported to be involved in cancer progression by promoting cell proliferation and epithelial–mesenchymal transition. However, the clinical significance and biological role of DDX5 in non-small-cell lung cancer (NSCLC) remain largely unknown. In this study, we examined the expression of DDX5 in clinical NSCLC samples, investigated its role in regulating NSCLC cell proliferation and tumorigenesis, and explored the possible molecular mechanism. We found that DDX5 was significantly overexpressed in NSCLC tissues as compared with the matched normal adjacent tissues. In addition, overexpression of DDX5 was associated with advanced clinical stage, higher Ki67 index, and shorter overall survival in NSCLC patients. Upregulation of DDX5 promoted proliferation of NSCLC cells in vitro and growth of NSCLC xenografts in vivo, whereas downregulation of DDX5 showed the opposite effects. Furthermore, DDX5 directly interacted with β-catenin, promoted its nuclear translocation, and co-activated the expression of cyclin D1 and c-Myc. β-catenin silencing significantly abrogated DDX5-induced cyclin D1 and c-Myc expression and proliferation in NSCLC cells. Interestingly, DDX5 and cyclin D1 expression followed positive correlation in the same set of NSCLC samples. These findings indicated that DDX5 played an important role in the proliferation and tumorigenesis of NSCLC cells by activating the β-catenin signaling pathway. Therefore, DDX5 may serve as a novel prognostic marker and potential therapeutic target in the treatment of NSCLC.

The DDX5/Dbp2 subfamily of DEAD‐box RNA helicases

“…DDX5 activates pro‐growth signaling pathways including Wnt, Notch, and mTOR pathways (Du et al, ; Lin et al, ; Taniguchi et al, ; Z. Wang et al, ; L. Yang et al, ). First, in colon cancer cells and NSCLCs, Tyr 593 ‐phosphorylated DDX5 is translocated to the cytoplasm to facilitate the nuclear translocation of β‐catenin, which activates Wnt target genes including Cyclin D1 and c‐Myc (Shin, Rossow, Grande, & Janknecht, ; Z. Wang et al, ; L. Yang et al, ; Yang, Lin, Zhao, Wang, & Liu, ). These Wnt targets then promote cell proliferation and tumorigenesis.…”

“…DDX5 activates pro-growth signaling pathways including Wnt, Notch, and mTOR pathways (Du et al, 2017;Lin et al, 2013;Taniguchi et al, 2016;Z. Wang et al, 2015;L.…”

“…Depletion of DDX5/DDX17 in many of these cancers inhibits the growth of tumor cells, suggesting requirement of DDX5/DDX17 in cancer development. Importantly, overexpression of DDX5 promotes growth of gastric cancers and non-small-cell lung cancer (NSCLC) cells both in vitro and in vivo, indicating that DDX5 may be a driver for cellular transformation (Du et al, 2017;Z. Wang et al, 2015).…”

Forkhead box N1 inhibits the progression of non-small cell lung cancer and serves as a tumor suppressor

“…By activating the β-catenin signaling pathway, DEAD-box helicase 5 promoted the proliferation and tumorigenesis of NSCLC (22). In addition, through promoting β-catenin degradation, Shisa3 was associated with prolonged survival times in lung cancer (23).…”

Extracellular superoxide dismutase and its role in cancer

“…MacroH2A1.1 increased SOD3 expression in 4T1 cells, while macroH2A1.2 decreased its expression [189]. Ddx5 and/or Ddx17 is overexpressed in a variety of solid cancers, such as breast, colon, prostate, non-small cell lung, head and neck, glioma, and leukemia [190–196]. Therefore, increases in Ddx5 and Ddx17 leading to higher macroH2A1.2 levels are an additional mechanism of EcSOD down-regulation in cancer.…”