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Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway

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Abstract

Epithelial-mesenchymal transition (EMT) leads to tumor dissemination and metastasis. Metadherin (MTDH) is an oncogene that plays an important role in metastasis regulation. This study tries to investigate the effect of MTDH gene up-regulation on the activation of EMT in colorectal cancer (CRC) cells and identify the role of NF-κB p65. The CaCO2 cells were divided into three groups: one control group of cultured CaCO2 cells (C1), and two groups of CaCO2 cells co-transfected using human MTDH expression plasmid with either siRNA targeting human NF-κB p65 or its negative control (C2 and C3 respectively). The gene modification was confirmed by qPCR and the effect of gene modification on CRC aggravation was studied. MTDH up-regulation significantly promoted CRC cell proliferation, activated anaerobic respiration (glucose consumption and lactate production), and increased gene expression of multidrug resistance gene (MDR1), Snail transcription factor and NF-κB p65, but decreased the gene expression of E-cadherin. Moreover, MTDH up-regulation led to a significant increase in the acquisition of surface markers of CRC stem cells. Interference with NF-κB p65 gene expression reversed the action of MTDH gene up-regulation on MDR1 and E-cadherin gene expression and anaerobic respiration. Moreover, NF-κB p65 interference significantly decreased MTDH-induced cell proliferation and acquisition of surface markers of CRC stem cells but didn’t affect the Snail transcription factor. MTDH-dependent EMT in CRC is activated via NF-κB p65 and is mediated by up-regulation of Snail. These results identify a pathway by which MTDH regulates NF-κB p65 induced EMT during CRC cell metastasis.

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Authors and Affiliations

  1. Biochemistry Department, Faculty of Pharmacy, Tanta University, Tanta, 31111, Egypt

    Nahla E. El-Ashmawy, Eman G. Khedr & Mariam A. Abo-Saif

  2. Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt

    Enas A. El-Zamarany

Authors
  1. Nahla E. El-Ashmawy
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  2. Enas A. El-Zamarany
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  3. Eman G. Khedr
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  4. Mariam A. Abo-Saif
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Correspondence to Mariam A. Abo-Saif.

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El-Ashmawy, N.E., El-Zamarany, E.A., Khedr, E.G. et al. Activation of EMT in colorectal cancer by MTDH/NF-κB p65 pathway. Mol Cell Biochem 457, 83–91 (2019). https://doi.org/10.1007/s11010-019-03514-x

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  • DOI: https://doi.org/10.1007/s11010-019-03514-x

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