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HGF/c-Met Overexpressions, but not Met Mutation, Correlates with Progression of Non-small Cell Lung Cancer

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Pathology & Oncology Research

Abstract

Hepatocyte Growth Factor (HGF) and its receptor c-Met are suggested to play an important role in progression of solid organ tumors by mediating cell motility, invasion and metastasis. Overexpression of HGF and c-Met have been shown in non-small-cell lung cancer (NSCLC). However, their role in tumor progression is not clearly defined. The aim of this study is to determine the role of HGF/c-Met pathway and its association with invasion related markers and clinicopathologic parameters in NSCLC. Immunohistochemical analysis was performed on 63 paraffin-embedded NSCLC tumor sections. The expressions of invasion related markers such as Matrix Metalloproteinases (MMPs) 2 and 9, Tissue Inhibitor Metalloproteinase (TIMP) 1 and 3 and RhoA were also examined. Co-expression of HGF/c-Met was significantly associated with lymph node invasion and TIMP-3 and RhoA overexpressions. There were positive correlation between TIMP-3 overexpression and advanced stage and negative correlation between RhoA overexpression and survival. DNA sequencing for Met mutations in both nonkinase and tyrosine kinase (TK) domain was established. A single nucleotide polymorphism (SNP) in sema domain and two SNPs in TK domain of c-Met were found. There was no statistically significant correlation between the presence of c-Met alterations and clinicopathologic parameters except shorter survival time in cases with two SNPs in TK domain. These results suggest that HGF/c-Met might exert their effects in tumor progression in association with RhoA and probably with TIMP-3. The blockade of the HGF/c-Met pathway with RhoA and/or TIMP-3 inhibitors may be an effective therapeutic target for NSCLC treatment.

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Abbreviations

HGF:

Hepatocyte Growth Factor

NSCLC:

Non-small cell lung cancer

MMP:

Matrix metalloproteinases

TIMP:

Tissue inhibitor of metalloproteinases

ECM:

Extracellular matrix

TK:

Tyrosine kinase

JM:

Juxtamembrane

TM:

Transmembrane

SNP:

Single nucleotide polymorphism

IHC:

Immunohistochemistry

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Acknowledgements

This study was supported by Dokuz Eylul University Research Foundation, grant number 04.KB-SAG.085. The authors wish to thank Assoc. Prof. Belgin Unal for excellent help in statistical analysis.

Disclosure statement

All authors have no financial and personal relationships with other people or organizations that could inappropriately influence (bias) their work. All authors have read and approved the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Dokuz Eylul University Medical School, Inciralti, 35340, Izmir, Turkey

    Mukaddes Gumustekin

  2. Department of Pathology, Dokuz Eylul University Medical School, Inciralti, 35340, Izmir, Turkey

    Aydanur Kargi & Cagnur Ulukus

  3. Department of Medical Biology and Genetics, Dokuz Eylul University Medical School, Inciralti, 35320, Izmir, Turkey

    Gulay Bulut, Aysim Gozukizil & Nese Atabey

  4. Department of Medical Oncology, Dokuz Eylul University Medical School, Inciralti, 35340, Izmir, Turkey

    Ilhan Oztop

  5. Medical Biology and Genetics, Dokuz Eylul University School of Medicine, Inciralti, 35340, Izmir, Turkey

    Nese Atabey

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  1. Mukaddes Gumustekin
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  2. Aydanur Kargi
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Correspondence to Nese Atabey.

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Gumustekin, M., Kargi, A., Bulut, G. et al. HGF/c-Met Overexpressions, but not Met Mutation, Correlates with Progression of Non-small Cell Lung Cancer. Pathol. Oncol. Res. 18, 209–218 (2012). https://doi.org/10.1007/s12253-011-9430-7

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  • DOI: https://doi.org/10.1007/s12253-011-9430-7

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