DcR3 induces epithelial-mesenchymal transition through activation of the TGF-β3/SMAD signaling pathway in CRC

Abstract

Decoy receptor 3 (DcR3), a novel member of the tumor necrosis factor receptor (TNFR) family, was recently reported to be associated with tumorigenesis and metastasis. However, the role of DcR3 in human colorectal cancer (CRC) has not been fully elucidated. In this study, we found that DcR3 expression was significantly higher in human colorectal cancer tissues than in paired normal tissues, and that DcR3 expression was strongly correlated with tumor invasion, lymph node metastases and poor prognoses. Moreover, DcR3 overexpression significantly enhanced CRC cell proliferation and migration in vitro and tumorigenesis in vivo. Conversely, DcR3 knockdown significantly repressed CRC cell proliferation and migration in vitro, and DcR3 deficiency also attenuated CRC tumorigenesis and metastasis in vivo. Functionally, DcR3 was essential for TGF-β3/SMAD-mediated epithelial-mesenchymal transition (EMT) of CRC cells. Importantly, cooperation between DcR3 and TGF-β3/SMAD-EMT signaling-related protein expression was correlated with survival and survival time in CRC patients. In conclusion, our results demonstrate that DcR3 may be a prognostic biomarker for CRC and that this receptor facilitates CRC development and metastasis by participating in TGF-β3/SMAD-mediated EMT of CRC cells.

DcR3 induces proliferation, migration, invasion, and EMT in gastric cancer cells via the PI3K/AKT/GSK-3β/β-catenin signaling pathway

“…It has also been reported that DcR3 regulates tumor metastasis by mediating the EMT of colorectal cancer and HCC cells, which is consistent with our findings. 12 , 13 Together with our results, these observations indicate that DcR3 facilitates the occurrence of EMT.…”

“… 11 Recent studies reported that DcR3 is closely related with metastasis of various cancers. 12 , 13 However, the specific mechanisms whereby DcR3 participates in the EMT process remain unclear. Therefore, in this study, we explored the role of DcR3 in tumorigenesis and EMT and established a theoretical basis for DcR3-targeted therapy for GC.…”

Advanced oxidation protein products induce hepatocyte epithelial–mesenchymal transition via a ROS‐dependent, TGF‐β/Smad signaling pathway

“…TGF‐β ligand first binds to TGF‐βRII at epithelial cells membrane, which allows for the phosphorylation of TGF‐βRI. The TGF‐βR I kinase subsequently activates downstream signaling through phosphorylating Smad2 and Smad3, which oligomerize with Smad4 and then translocate to the nucleus to regulate transcriptional gene expression (Yang et al, ; Muthusamy et al, ; Liu et al, ). Although previous reports have established that TGF‐β signaling participates in oxidative stress‐triggered hepatic stellate cell EMT and liver fibrosis, whether TGF‐β/Smad signaling is involved in hepatocytes EMT is not well understood.…”

PCDHGA9 acts as a tumor suppressor to induce tumor cell apoptosis and autophagy and inhibit the EMT process in human gastric cancer

“…TGF-β signaling is activated when the cytokine interacts with transmembrane receptors of type I (TGFβ RI) or type II (TGFβ RII) 18 . Interaction with TGFβ RI leads to the phosphorylation of Smad2/3, which translocates to the nucleus and regulates the expression of target genes, such as Snal1, Slug, and ZEB1 19 . We demonstrated that the overexpression of PCDHGA9 could reduce the phosphorylation of Smad2/3 and suppress the nuclear translocation of pSmad2/3 to regulate the transcription of Snail1.…”