Expression of the c-MET, HGF and VEGF biomarkers in intestinal and diffuse gastric cancer in the Brazilian population: a pilot study for the standardization of the quantitative PCR technique

Springer Science and Business Media LLC - Tập 37 - Trang 1-8 - 2017
Bianca Della Croce Vieira Cota1, Karine Sampaio Lima1, André Márcio Murad2, Marcelo Antônio Pascoal Xavier3, Mônica Maria Demas Álvares Cabral3, Luiz Gonzaga Vaz Coelho1,2
1Alfa Institute of Gastroenterology, Clinics Hospital, Federal University of Minas Gerais, Belo Horizonte, Brazil
2Department of Internal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
3Department of Pathology, Faculty of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil

Tóm tắt

Gastric carcinoma (GC) is the third leading cause of death among malignant tumors worldwide, causing approximately 900,000 deaths/year. Changes in oncogenes that encode tyrosine kinase receptors play an important role in the pathogenesis of GC. MET gene is a proto-oncogene that encodes a tyrosine kinase receptor c-MET and it is required for embryonic development and tissue repair. The hepatocyte growth factor (HGF) is the only known ligand for c-Met receptor. The MET oncogene activation suppresses apoptosis and promotes the survival, proliferation, migration, differentiation and angiogenesis of cells. Among the angiogenic factors, VEGF is the main regulator. Its biological function includes the promotion of endothelial cells mitosis to stimulate cells proliferation. These biomarkers expression in GC is relatively recent and population-based studies are required to define the expression pattern. The aim of this study was to determine qPCR technical standardization to evaluate quantitatively, in paraffin tissue samples, the presence of gene 23 expression of the MET, HGF and VEGF in diffuse and intestinal GC types. Twenty GC patients were studied, 10 patients were intestinal-type GC (average age 72.1 years) and 10 diffuse-type (average age 50.1 years). In all patients, tissue samples were analyzed from the tumor and distant areas of the tumor tissue. The relative expressions of the tumor markers c-Met, HGF and VEGF were performed by qPCR technique by comparing tumor and non-tumoral samples and they were normalized with the GAPDH constitutive gene. Statistical analysis was performed through T-test. For c-Met, 18/20 (90%) patients expressed the marker and 9/20 (45%) overexpressed this gene, in which three were intestinal-type GC and six were diffuse-type GC. For HGF, only 7/20 (35%) patients expressed this gene and it was overexpressed in 4/20 (20%), in which two were intestinal-type GC and two were diffuse-type GC. For VEGF, 20/20 (100%) patients expressed this marker and in 12/20 (60%) were observed overexpression, in which eight patients had diffuse-type GC and four had intestinal-type GC. qPCR technique was standardized and suitable for expression analysis of the three biomarkers using paraffin embedded tissue samples. Further studies should be carried out to characterize the expression pattern of these biomarkers in GC in the Brazilian population.

Tài liệu tham khảo

Parkin D, et al. Global cancer statistics. CA Cancer J Clin. 2005;55:74–108. Instituto Nacional do Câncer. Inca. Estimativa/2014. Disponível em http://www1.inca.gov.br. Acesso em 14 Jan 2016. Laurén P. The Two Histological Main Types of Gastric Carcinoma: Diffuse and So-Called Intestinal-Type Carcinoma. An Attempt at a Histo-Clinical Classification. Acta Pathol Microbiol Scand. 1965;64:31–49. Laurén P. Histogenesis of intestinal and diffuse types of gastric carcinoma. Scand J Gastroenterol Suppl. 1991;180:160–4. Laurén P, Nevalainen T. Epidemiology of intestinal and diffuse types of gastric carcinoma. A time-trend study in Finland with comparison between studies from high- and low-risk areas. Cancer. 1993;71:2926–33. Correa P, Piazuelo M. Natural history of Helicobacter pylori infection. Dig Liver Dis. 2008;40:490–6. Tahara E. Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004;157:327–49. TCGA. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–9. Yoshida WB. Angiogenesis, arteriogenesis and vasculogenesis: treatment of the future for lower limb critical ischemia? J Vasc Bras. 2005;4:316–8. Folkman J, Long DM Jr, Becker FF. Growth and metastasis of tumor in organ culture. Cancer. 1963;16:453–67. Catalano V, Labianca R, Beretta GD, et al. Gastric cancer. Crit Rev Oncol Hematol. 2009;71:127–64. Badescu A, Georgescu CV, Vere CC, et al. Correlations between Her2 oncoprotein, VEGF expression, MVD and clinicopathological parameters in gastric cancer. Rom J Morphol Embryol. 2012;53(4):997–1005. Sierra J, Tsao MS. c-MET as a potential therapeutic target and biomarker in cancer. Ther Adv Med Oncol. 2011;3:S21–35. Gentile A, Trusolino L, Comoglio PM. The Met tyrosine kinase receptor in development and cancer. Cancer Metastasis Rev. 2008;27:85–94. Hack S, Bruey JM, Koeppen H. HGF/MET-directed therapeutics in gastroesophageal cancer: a review of clinical and biomarker development. Oncotarget. 2014;5(10):2866–80. Begnami MD, Fregnani JH, Brentani H, et al. Identification of protein expression signatures in gastric carcinomas using clustering analysis. J Gastroenterol Hepatol. 2012;2(2):378–84. Toiyama Y, Yasuda H, Saigusa S, et al. Co-expression of hepatocyte growth factor and c-Met predicts peritoneal dissemination established by autocrine hepatocyte growth factor/c-Met signaling in gastric cancer. Int J Cancer. 2012;130:2912–21. Nakajima M, Sawada H, Yamada Y, et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer. 1999;85(9):1894–902. Tanigushi K, Yonemura Y, Nojima N, et al. The relation between the growth patterns of gastric carcinoma and the expression of hepatocyte growth factor receptor (c-met), autocrine motility factor receptor, and urokinase-type plasminogen activator receptor. Cancer. 1998;82(11):2112–22. Amemiya H, Menolascino F, Peña A. Papel de la expresión del receptor c-Met em la progresión del câncer gástrico. Invest Clin. 2010;51(3):369–80. Tahara E. Genetic alterations in human gastrointestinal cancers. The application to molecular diagnosis. Cancer. 1995;75:1410–7. Lee H, Kim MA, Lee HS, et al. MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome. Br J Cancer. 2012;107:325–33. Janjigian YY, Tang LH, Coit DG, et al. MET Expression and Amplification in Patients with Localized Gastric Cancer. Cancer Epidemiol Biomarkers Prev. 2011;20:1021–7. Inokushi M, Otsuki S, Fujimori Y, et al. Clinical significance of MET in gastric cancer. World J Gastrointest Oncol. 2015;7(11):317–27. Huang TJ, Wang JY, Lin SR, et al. Overexpression of the c-met Protooncogene in Human Gastric Carcinoma- correlation to clinical features. Acta Oncol. 2001;40(5):638–43. Jo M, Stolz DB, Esplen JE, Dorko K, et al. Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem. 2000;275(12):8806–11. Kawakami H, Okamoto I. MET-targeted therapy for gastric cancer: the importance of a biomarker-based strategy. Gastric Cancer. 2016;19:687–95. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992;24:6735–40.