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
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.
Departamento de Patologia Oral, Faculdade de Odontologia da Universidade de São Paulo, São Paulo, Brazil.
Diabetol Metab Syndr. 2015 Oct 1;7:84. doi: 10.1186/s13098-015-0079-3. eCollection 2015.
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.
胰岛素瘤是最常见的功能性胰腺神经内分泌肿瘤，但其组织病理学特征无法预测其生物学行为。为了更好地理解胰岛β细胞肿瘤发生过程中涉及的分子机制，本研究评估了属于肝细胞生长因子及其受体（HGF/MET）系统的基因表达，即MET、HGF；HGFAC和ST14（分别编码HGF激活剂和matriptase，两种催化前HGF转化为活性HGF的丝氨酸蛋白酶）；以及SPINT1和SPINT2（分别编码Kunitz型1和2丝氨酸肽酶抑制剂，HGF激活剂和matriptase的两种抑制剂）。
采用定量实时逆转录聚合酶链反应评估24例散发性胰岛素瘤中靶基因的RNA表达：15例1级（G1）、6例2级（G2）和3例肝转移瘤。通过对第2、10、14、16、17和19外显子的直接测序来搜索MET基因的体细胞突变。
在3例肝转移瘤中观察到MET的过表达，同时编码HGF和matriptase的基因上调，SPINT1下调。MET RNA表达与Ki-67增殖指数呈正相关，而SPINT1表达与有丝分裂指数呈负相关。MET基因未发现体细胞突变。
HGF、其激活剂（matriptase）及其特异性受体（MET）表达增加，同时一种强效matriptase抑制剂（SPINT1）表达降低，最终可能促进胰岛素瘤的肿瘤进展和转移。
