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Crosstalk between MMP-13, CD44, and TWIST1 and its role in regulation of EMT in patients with esophageal squamous cell carcinoma

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Abstract

Matrix metalloproteinases (MMPs) play key roles in epithelial-mesenchymal transition (EMT) for the development of cancer cell invasion and metastasis. MMP-13 is an extracellular matrix (ECM)-degrading enzyme that plays crucial roles in angiogenesis, cell cycle regulation, niche maintenance, and transforming squamous epithelial cells in various tissues. CD44, a transmembrane glycoprotein expressed on esophageal tumor cells, is required for EMT induction and invasion in esophageal squamous cell carcinoma (ESCC). The transcription factor TWIST1, as EMT and stemness marker, regulates MMPs expression and is identified as the downstream target of CD44. In this study, we aimed to investigate the probable interplay between the expression of key genes contributing to ESCC development, including MMP-13, TWIST1, and CD44 with clinical features for introducing novel diagnostic and therapeutic targets in the disease. The gene expression profiling of MMP-13, TWIST1, and CD44 was performed using quantitative real-time PCR in tumor tissues from 50 ESCC patients compared to corresponding margin non-tumoral tissues. Significant overexpression of MMP-13, CD44S, CD44V3, CD44V6, and TWIST1 were observed in 74%, 36%, 44%, 44%, and 52% of ESCC tumor samples, respectively. Overexpression of MMP-13 was associated with stage of tumor progression, metastasis, and tumor location (P < 0.05). There was a significant correlation between TWIST1 overexpression and grade (P < 0.05). Furthermore, overexpression of CD44 variants was associated with stage of tumor progression, grade, tumor invasion, and location (P < 0.05). The results indicated the significant correlation between concomitant expression of MMP-13/TWIST1, TWIST1/CD44, and CD44/MMP-13 with each other in a variety of clinicopathological traits, including depth of tumor invasion, tumor location, stage of tumor, and lymph node involvement in ESCC tissue samples (P < 0.05). Collectively, our results indicate that the TWIST1-CD44-MMP-13 axis is involved in tumor aggressiveness, proposing these genes as regulators of EMT, diagnostic markers, and therapeutic targets in ESCC.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ESCC:

Esophageal squamous cell carcinoma

ECM:

Extracellular matrix

MMPs:

Matrix metalloproteinases

BM:

Basement membrane

TIMPs:

Tissue inhibitors of metalloproteinase

MMP-1:

Collagenase-3

TNF-α:

Tumor necrosis factor

IL-1:

Interleukin-1

EGF:

Epidermal growth factor

HGF:

Hepatocyte growth factor

FGFs:

Fibroblast growth factors

TGF:

Transforming growth factor

EMT:

Epithelial-mesenchymal transition

TFs:

Transcription factors

EC:

Esophageal cancer

CSCs:

Cancer stem cells

MUC1:

Mucin 1

MMP-14:

MT1-MMP

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Acknowledgements

We gratefully acknowledge our colleagues at the Human Division of Human Genetics, Immunology Research Institute, Avicenna Research Institute (Mashhad University of Medical Sciences) for their scientific and technical supports.

Funding

This study was supported by a Grant from Vice chancellor of Mashhad University of Medical Sciences (#941435).

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Authors and Affiliations

  1. Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Reihaneh Alsadat Mahmoudian, Maryam Lotfi Gharaie, Ali Alasti & Mehran Gholamin

  2. Division of Physiology, Department of Basic Science, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran

    Maryam Lotfi Gharaie

  3. Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Mohammad Reza Abbaszadegan

  4. Department of Biology, Damghan Branch, Islamic Azad University, Damghan, Iran

    Mohammad Mahdi Forghanifard

  5. Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

    Atena Mansouri

  6. Innovated Medical Research Center and Department of Immunology, Mashhad Branch, Islamic Azad University, Mashhad, Iran

    Atena Mansouri

  7. Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, P.O.Box 345-91357, Mashhad, Iran

    Mehran Gholamin

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  1. Reihaneh Alsadat Mahmoudian
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  2. Maryam Lotfi Gharaie
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  3. Mohammad Reza Abbaszadegan
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  4. Ali Alasti
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  5. Mohammad Mahdi Forghanifard
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Correspondence to Mehran Gholamin.

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Mahmoudian, R.A., Gharaie, M.L., Abbaszadegan, M.R. et al. Crosstalk between MMP-13, CD44, and TWIST1 and its role in regulation of EMT in patients with esophageal squamous cell carcinoma. Mol Cell Biochem 476, 2465–2478 (2021). https://doi.org/10.1007/s11010-021-04089-2

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