MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFβ/SMAD Signaling Pathway in Colorectal Cancer Metastasis

Abstract

Background/Aims: Colorectal cancer (CRC) is a malignancy that has high morbidity and mortality and is initiated from accumulative genetic events. Although much effort has been made to elucidate the genetic mechanism underlying this disease, it still remains unknown. Here, we discovered a novel role for multiple epidermal growth factor-like domains protein 6 (MEGF6) in CRC, namely, that it induces the epithelial-to-mesenchymal transition (EMT) to promote CRC metastasis via the transforming growth factor beta (TGFβ)/SMAD signaling pathway. Methods: RNA sequencing data from the Gene Expression Omnibus database were analyzed using R software. Based on The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort, the clinical significance of MEGF6 was investigated. HCT8R, HCT116, and LoVo CRC cells were transfected with small interfering RNA against MEGF6, and their proliferation and sensitivity to fluorouracil were evaluated with the MTT cell proliferation and colony formation assays. Proteins associated with cell growth were detected by western blot analysis. The apoptosis of cells was evaluated by Annexin V/propidium iodide staining, and transwell assays were performed to assess the involvement of MEGF6 in cell migration. Markers of EMT and TGFβ/SMAD signaling were evaluated by quantitative PCR and western blotting, and the correlation between MEGF6 and these markers was assessed in the TCGA colon and renal adenocarcinoma cohort. Results: The results showed that MEGF6 was upregulated in HCT8R cells. In addition, MEGF6 was significantly overexpressed in tumor tissue and predicted a poor survival in the TCGA-COAD cohort. Moreover, MEGF6 accelerated CRC cell growth and inhibited apoptosis, and promoted CRC metastasis by inducing the EMT. Finally, we found that TGFβ/SMAD signaling triggered the expression of Slug, which regulates the MEGF6-mediated EMT. Conclusions: MEGF6 may serve as an oncogene to promote cell proliferation and inhibit apoptosis. MEGF6 can also accelerate cell migration via TGFβ/SMAD signaling-mediated EMT.

Planarian EGF repeat-containing genes megf6 and hemicentin are required to restrict the stem cell compartment

“…Curiously, this has led to the focus on ced-1/Draper/MEGF10/ 11 homologs, and MEGF6 genes have gone unstudied, with almost no functional data (even in C. elegans). Little is known about the role of MEGF6 in any system, though it has been shown to promote the metastasis of colorectal cancer by inducing EMT [49]. Given the phenotypes observed with knockdown of planarian megf6, we hypothesize that MEGF6 may have a role in regulating EMT migration through an ECM-based mechanism as described here for planarians.…”

Neuropilin 1 modulates TGF‑β1‑induced epithelial‑mesenchymal transition in non‑small cell lung cancer

“…EMT plays a vital role in tumor metastasis as is evident by the upregulated expression of N-cadherin and Vimentin, while the expression level of E-cadherin is downregulated (34). TGF-β/Smad signaling pathway is an important driver in promoting the EMT process via activating the canonical pathway as with Smad family members or non-canonical signaling molecules such as Rho kinase (35,36). TGF-β1-induced EMT has been implicated in diabetic kidney diseases, fibrosis phenotype and tumor cell Following serum starvation for 24 h, stable NRP1-silenced A549 and H226 cells were treated with or without TGF-β1 (5 ng/ml) for 48 h. The expression of p-Smad3, Smad3, Snail, MMP2, MMP9, N-cadherin, Vimentin was analyzed by western blot analysis.…”

Copy Number Variation Pattern for Discriminating MACROD2 States of Colorectal Cancer Subtypes

“…This position is in the intron region of multiple EGF-like-domains 6 (MEGF6) gene, which was reported to play a critical role in cell adhesion and involved in many disorders of neural system development (Sunnerhagen et al, 1993). Recent publications have confirmed that MEFG6 can promote the epithelia-to-mesenchymal transition in CRC metastasis (Hu et al, 2018). This gene is also significantly upregulated in tumor tissue and results in the poor survival of a colon adenocarcinoma cohort.…”