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

Murat Cde B, da Rosa PW, Fortes MA, Corrêa L, Machado MC, Novak EM, Siqueira SA, Pereira MA, Corrêa-Giannella ML, Giannella-Neto D, Giorgi RR - Diabetol Metab Syndr (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

mRNA expression values of MET (a), HGF (b), ST14 (c), SPINT1 (d), and SPINT2 (e) in insulinomas graded according to 2014 ENETS/WHO classification (G1, G2 and hepatic metastases). Box diagram comparing relative mRNA expression levels of genes; the horizontal line within the box plot represents the median value, the box plot limits refer to 25th–75th percentiles, and the box plot bars include the 10th–90th percentiles for mRNA levels
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Fig1: mRNA expression values of MET (a), HGF (b), ST14 (c), SPINT1 (d), and SPINT2 (e) in insulinomas graded according to 2014 ENETS/WHO classification (G1, G2 and hepatic metastases). Box diagram comparing relative mRNA expression levels of genes; the horizontal line within the box plot represents the median value, the box plot limits refer to 25th–75th percentiles, and the box plot bars include the 10th–90th percentiles for mRNA levels

Mentions: As shown in Fig. 1, a higher expression of MET (P = 0.0115, Panel A), HGF (P = 0.0183, Panel B) and ST14 (P = 0.0453, Panel C) mRNA was observed in the three metastases in comparison to G1 insulinomas. No HGFAC gene expression was detected in any studied tumoral sample (data not shown). The expression of SPINT1 mRNA (Panel D) was lower in the three metastases in comparison to G1 insulinomas (P = 0.0250), whereas no difference was detected in SPINT2 gene expression (Panel E). No statistically significant differences were observed between G1 and G2 insulinomas for any of the studied genes.Fig. 1


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

Murat Cde B, da Rosa PW, Fortes MA, Corrêa L, Machado MC, Novak EM, Siqueira SA, Pereira MA, Corrêa-Giannella ML, Giannella-Neto D, Giorgi RR - Diabetol Metab Syndr (2015)

mRNA expression values of MET (a), HGF (b), ST14 (c), SPINT1 (d), and SPINT2 (e) in insulinomas graded according to 2014 ENETS/WHO classification (G1, G2 and hepatic metastases). Box diagram comparing relative mRNA expression levels of genes; the horizontal line within the box plot represents the median value, the box plot limits refer to 25th–75th percentiles, and the box plot bars include the 10th–90th percentiles for mRNA levels
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4591639&req=5

Fig1: mRNA expression values of MET (a), HGF (b), ST14 (c), SPINT1 (d), and SPINT2 (e) in insulinomas graded according to 2014 ENETS/WHO classification (G1, G2 and hepatic metastases). Box diagram comparing relative mRNA expression levels of genes; the horizontal line within the box plot represents the median value, the box plot limits refer to 25th–75th percentiles, and the box plot bars include the 10th–90th percentiles for mRNA levels
Mentions: As shown in Fig. 1, a higher expression of MET (P = 0.0115, Panel A), HGF (P = 0.0183, Panel B) and ST14 (P = 0.0453, Panel C) mRNA was observed in the three metastases in comparison to G1 insulinomas. No HGFAC gene expression was detected in any studied tumoral sample (data not shown). The expression of SPINT1 mRNA (Panel D) was lower in the three metastases in comparison to G1 insulinomas (P = 0.0250), whereas no difference was detected in SPINT2 gene expression (Panel E). No statistically significant differences were observed between G1 and G2 insulinomas for any of the studied genes.Fig. 1

Bottom Line: 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.

View Article: PubMed Central - PubMed

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.

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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus