title: Differential expression of genes encoding proteins of the HGF/MET system in insulinomas.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), Av. Dr. Arnaldo, 455, 01246-903 São Paulo, SP Brazil.
authors.forename: Cahuê De Bernardis
authors.initials: Cde B
authors.lastname: Murat
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), Av. Dr. Arnaldo, 455, 01246-903 São Paulo, SP Brazil.
authors.forename: Paula Waki Lopes
authors.initials: PW
authors.lastname: da Rosa
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), Av. Dr. Arnaldo, 455, 01246-903 São Paulo, SP Brazil.
authors.forename: Maria Angela Henriques Zanella
authors.initials: MA
authors.lastname: Fortes
authors.affiliation: Departamento de Patologia Oral, Faculdade de Odontologia da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Luciana
authors.initials: L
authors.lastname: Corrêa
authors.affiliation: Laboratório de Emergências Clínicas (LIM-51) da FMUSP, São Paulo, Brazil.
authors.forename: Marcel Cerqueira Cesar
authors.initials: MC
authors.lastname: Machado
authors.affiliation: Laboratório de Biologia Molecular da Fundação Pró-Sangue Hemocentro de São Paulo, São Paulo, Brazil.
authors.forename: Estela Maria
authors.initials: EM
authors.lastname: Novak
authors.affiliation: Divisão de Patologia do HC-FMUSP, São Paulo, Brazil.
authors.forename: Sheila Aparecida Coelho
authors.initials: SA
authors.lastname: Siqueira
authors.affiliation: Divisão de Endocrinologia do HC-FMUSP, São Paulo, Brazil.
authors.forename: Maria Adelaide Albergaria
authors.initials: MA
authors.lastname: Pereira
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), Av. Dr. Arnaldo, 455, 01246-903 São Paulo, SP Brazil ; Centro de Terapia Celular e Molecular (NUCEL/NETCEM) da FMUSP, São Paulo, Brazil.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Corrêa-Giannella
authors.affiliation: Programa de Pós-Graduação em Medicina, Universidade Nove de Julho-UNINOVE, São Paulo, Brazil.
authors.forename: Daniel
authors.initials: D
authors.lastname: Giannella-Neto
authors.affiliation: Laboratório de Endocrinologia Celular e Molecular (LIM-25) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), Av. Dr. Arnaldo, 455, 01246-903 São Paulo, SP Brazil ; Programa de Pós Graduação em Ciências da Saúde, Universidade de Santo Amaro (UNISA), São Paulo, Brazil.
authors.forename: Ricardo Rodrigues
authors.initials: RR
authors.lastname: Giorgi
keywords: Gene expression; Hepatocyte growth factor; Insulinoma; MET receptor; Somatic mutation