Alterations Of MET-HGF Pathway In Esophageal Squamous Cell Carcinoma
Haonne ABBOUD, Instituto Nacional de Câncer (INCA), Brazil
GONZAGA I. 1
, PINTO L. 1
, LIMA S. 1
1 Programa de Carcinogênese Molecular, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Esophageal cancer is among the most incident and lethal malignancies in the world and presents two main histological subtypes. Between them, squamous cell carcinoma of the esophagus (ESCC) corresponds to 80% of the cases. The development of ESCC in Brazil has been extensively correlated with tobacco and alcohol, but the molecular mechanisms involved are poorly understood. Among the most promising signaling pathways in gastrointestinal tumors, the hepatocyte growth factor (HGF) pathway and its receptor MET stands out. Thus, the aim of this study is to evaluate whether alterations of this pathway could contribute to ESCC development. To this end, tumor and normal surrounding tissue were collected from thirty patients diagnosed with ESCC. The evaluation of HGF and MET expression was performed by RT-qPCR using primers that discriminate the two splicing variants of MET. The methylation status of MET intragenic CpG sites was assessed by pyrosequencing. Only variant 2 of MET showed a significant variation in expression, which was increased in tumors. Thus, this variant was chosen as the focus of our study. From a ROC curve analysis, it was observed that the differential expression of this variant was able to distinguish with 93.1% of sensitivity and 86.21% of specificity tumors from surrounding tissue. We also performed the analysis of HGF expression and found its greatest expression in tumor tissue compared with its surrounding mucosa. The methylation analysis of MET intragenic CpG sites revealed a hypermethylation in ESCC. Thus, our data suggest that both the pathway receptor MET and its ligand HGF are upregulated in ESCC, which may represent potential diagnostic markers and/or new therapeutic targets. Furthermore, we show for the first time a deregulation of DNA methylation in MET gene body, which could be correlated with a preferential expression of splicing variant 2. Funding sources: Ministério da Saúde, CNPq, FAPERJ.