title: HGF/c-Met overexpressions, but not met mutation, correlates with progression of non-small cell lung cancer.
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.
authors.affiliation: Department of Pharmacology, Dokuz Eylul University Medical School, Inciralti, 35340, Izmir, Turkey.
authors.forename: Mukaddes
authors.initials: M
authors.lastname: Gumustekin
authors.forename: Aydanur
authors.initials: A
authors.lastname: Kargi
authors.forename: Gulay
authors.initials: G
authors.lastname: Bulut
authors.forename: Aysim
authors.initials: A
authors.lastname: Gozukizil
authors.forename: Cagnur
authors.initials: C
authors.lastname: Ulukus
authors.forename: Ilhan
authors.initials: I
authors.lastname: Oztop
authors.forename: Nese
authors.initials: N
authors.lastname: Atabey
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D015153:Blotting, Western; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D018450:Disease Progression; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; C066737:RHOA protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020742:rhoA GTP-Binding Protein