Differential expression of genes encoding proteins of the HGF/MET system in insulinomas.

Murat, Cahuê De Bernardis, da Rosa, Paula Waki Lopes, Fortes, Maria Angela Henriques Zanella, Corrêa, Luciana, Machado, Marcel Cerqueira Cesar, Novak, Estela Maria, Siqueira, Sheila Aparecida Coelho, Pereira, Maria Adelaide Albergaria, Corrêa-Giannella, Maria Lucia, Giannella-Neto, Daniel, Giorgi, Ricardo Rodrigues, Cahuê De Bernardis Murat, Paula Waki Lopes Rosa, Maria Angela Henriques Zanella Fortes, Luciana Corrêa, Marcel Cerqueira Cesar Machado, Estela Maria Novak, Sheila Aparecida Coelho Siqueira, Maria Adelaide Albergaria Pereira, Maria Lucia Corrêa-Giannella, Daniel Giannella-Neto, Ricardo Rodrigues Giorgi

Insulinomas are the most common functional pancreatic neuroendocrine tumors, whereas histopathological features do not predict their biological behaviour. In an attempt to better understand the molecular processes involved in the tumorigenesis of islet beta cells, the present study evaluated the expression of genes belonging to the hepatocyte growth factor and its receptor (HGF/MET) system, namely, MET, HGF; HGFAC and ST14 (encode HGF activator and matriptase, respectively, two serine proteases that catalyze conversion of pro-HGF to active HGF); and SPINT1 and SPINT2 (encode serine peptidase inhibitors Kunitz type 1 and type 2, respectively, two inhibitors of HGF activator and of matriptase). Quantitative real-time reverse transcriptase polymerase chain reaction was employed to assess RNA expression of the target genes in 24 sporadic insulinomas: 15 grade 1 (G1), six grade 2 (G2) and three hepatic metastases. Somatic mutations of MET gene were searched by direct sequencing of exons 2, 10, 14, 16, 17 and 19. Overexpression of MET was observed in the three hepatic metastases concomitantly with upregulation of the genes encoding HGF and matriptase and downregulation of SPINT1. A positive correlation was observed between MET RNA expression and Ki-67 proliferation index while a negative correlation was detected between SPINT1 expression and the mitotic index. No somatic mutations were found in MET gene. The final effect of the increased expression of HGF, its activator (matriptase) and its specific receptor (MET) together with a decreased expression of one potent inhibitor of matriptase (SPINT1) is probably a contribution to tumoral progression and metastatization in insulinomas.