Abstract
BackgroundRecent studies have reported the involvement of microRNA-29 (miR-29) family members in human cancers through their ability to regulate cellular functions. The present study investigated biological function of miR-29b in colorectal cancer (CRC).MethodsCRC tissues and adjacent normal tissues were collected and the expression of ETV4 and miR-29b in the tissues were identified. The relationship between ETV4 and miR-29b or ETV4 expression and the EGFR promoter was identified using dual-luciferase reporter gene and CHIP assays. The proliferation, invasion, migration, and apoptosis of CRC HCT116 cells were assayed using MTT assay, Scratch test, Transwell assay, and flow cytometry, respectively. Also, expression of epithelial-mesenchymal transition (EMT) markers, angiogenic factors, and vasculogenic mimicry formation were evaluated using RT-qPCR and Western blot.ResultsETV4 was upregulated, while miR-29b expression was decreased in CRC tissues. ETV4 was identified as a target gene of miR-29b, which in turn inactivated the ERK signaling pathway by targeting ETV4 and inhibiting EGFR transcription. Transfection with miR-29b mimic, siRNA-ETV4, or ERK signaling pathway inhibitor U0126 increased expression of E-cadherin and TSP-1, and CRC cell apoptosis, yet reduced expression of ERK1/2, MMP-2, MMP-9, Vimentin, and VEGF, as well as inhibiting EMT, angiogenesis, and CRC cell migration and invasion. The EMT, angiogenesis and cancer progression induced by miR-29b inhibitor were reversed by siRNA-mediated ETV4 silencing.ConclusionsmiR-29b suppresses angiogenesis and EMT in CRC via the ETV4/ERK/EGFR axis.
Highlights
Recent studies have reported the involvement of microRNA-29 family members in human cancers through their ability to regulate cellular functions
The protein-protein interaction (PPI) network (Fig. 1c) showed that the disease genes interacted closely with each other in the regulatory network and that ETS variant 4 (ETV4) was the candidate presenting the highest correlation with diseased genes or other differentially expressed genes (DEGs)
According to the top 100 DEGs in GSE89076, the heatmap of DEGs was drawn (Fig. 1d), which showed that ETV4 was expressed higher in colorectal cancer (CRC) tissues than in adjacent normal tissues
Summary
Recent studies have reported the involvement of microRNA-29 (miR-29) family members in human cancers through their ability to regulate cellular functions. A previous study has revealed that the transcription factor E26 transformation-specific-1 (ETS1) could affect disease progression in patients with non-small-cell lung cancer by up-regulating expression of miR-29b in the immune-evasion disease subtype [9]. The inhibition of ERK provoked a reduction in the mRNA expression of ETV4 in melanoma cells occurs [13]. Despite these conflicting findings, the activation of the ERK signaling pathway can result in epithelial-mesenchymal transition (EMT) in CRC [14]
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