NDRG1 attenuates epithelial–mesenchymal transition of nasopharyngeal cancer cells via blocking Smad2 signaling

Abstract

N-myc downstream-regulated gene 1 (NDRG1) has been implicated in tumorigenesis and metastasis in different cancers. However, its role in nasopharyngeal carcinoma remains unknown. We found that NDRG1 expression level was high in nasopharyngeal cancer 5–8F cells but low in 5–8F-LN cells with lymphatic metastasis potential. Knockdown of NDRG1 by shRNA promoted 5–8F cell proliferation, migration, and invasion in vitro and its tumorigenesis in vivo. Moreover, NDRG1 deficiency induced an epithelial-mesenchymal transition (EMT) of 5–8F cells as shown by an attenuation of E-cadherin and an induction of N-cadherin and vimentin expression. NDRG1 knockdown also enhanced Smad2 expression and phosphorylation. Smad2 signaling was attenuated in 5–8F cells but was significantly activated in 5–8F-LN cells. Knockdown of Smad2 restored E-cadherin but attenuated N-cadherin expression in NDRG1-deficient 5–8F cells, suggesting a reduction of EMT. Consistently, blockade of Smad2 in 5–8F-LN cells increased E-cadherin while diminishing N-cadherin and vimentin expression. These data indicate that Smad2 mediates the NDRG1 deficiency-induced EMT of 5–8F cells. In tumors derived from NDRG1-deficient 5–8F cells, E-cadherin expression was inhibited while vimentin and Smad2 were increased in a large number of cancer cells. Most importantly, NDRG1 expression was attenuated in human nasopharyngeal carcinoma tissues, resulted in a lower survival rate in patients. The NDRG1 was further decreased in the detached nasopharyngeal cancer cells, which was associated with a further reduced survival rate in patients with lymphatic metastasis. Taken together, these results demonstrated that NDRG1 prevents nasopharyngeal tumorigenesis and metastasis via inhibiting Smad2-mediated EMT of nasopharyngeal cells.

Silencing of Long Non-coding RNA SMAD5-AS1 Reverses Epithelial Mesenchymal Transition in Nasopharyngeal Carcinoma via microRNA-195-Dependent Inhibition of SMAD5

“…As a group of intracellular proteins, SMADs are involved in transforming growth factor beta (TGFβ) signaling in cancer progression and metastasis (12). A previous study has suggested that SMAD2 signaling is involved in the inhibition of EMT in NPC cells (13). Moreover, miR-145 overexpression has been found to inhibit invasion and metastasis in NPC cells by targeting SMAD3 (14).…”

Knockdown of NDRG1 promote epithelial-mesenchymal transition of colorectal cancer via NF-κB signaling

“…The role of NDRG1 as a metastasis suppressor in CRC has been explored. It is reported that NDRG1 was involved in the metastasis of tumor by inhibiting EMT . The anti‐metastatic activity of NDRG1 in CRC could occur through the down‐regulation of nuclear β‐catenin .…”

“…Our study suggested that NDRG1 involved in mCRC though EMT via NF‐κB signaling pathway. NDRG1 has been demonstrated to inhibit EMT and restore the epithelial markers levels though TGF‐β, Smad2 signaling, or Wnt/β‐catenin pathways . Recent study suggested that NDRG1 played a significant role in regulating cancer cell migration by inhibiting Src activity, which involved in EMT and the development of metastasis .…”

“…(D) Transwell invasion assays were performed to investigate that p65-siRNA reduced number of invasive cells. Ã P < 0.05, ÃÃ P < 0.01, ÃÃÃ P < 0.001. pathways [23,24,27]. Recent study suggested that NDRG1 played a significant role in regulating cancer cell migration by inhibiting Src activity, which involved in EMT and the development of metastasis [30].…”

Discovering relationships between nuclear receptor signaling pathways, genes, and tissues in Transcriptomine

“…The potential role of NDRG1 in resistance of gastric cancer cells to MET pathway inhibition implicated by these data points is suggested by the role of NDRG1 in multidrug resistance in neuroblastoma cells (102). Moreover, its stabilization of the epithelial state in nasopharyngeal cancer cells (103) is consistent with the association between resistance to the MET inhibitor KRC-108 and transition to an epithelial phenotype (104). The Transcriptomine NDRG1 Regulation Report (https://goo.gl/ F76hnk) (accessed by clicking on the Transcriptomine query link in the FCI window of one of the NDRG1 data points) highlighted repression of Ndrg1 by the NR Rev-erbAa/Nr1d1 (data file S1, Query 17) (105,106).…”