The Importance of the RAS Interacting with the HGF/C-Met Receptor System in Hypertensive Type 2 Diabetes Mellitus.

The classic renin-angiotensin system (RAS) is described as a circulating hormone system with primary roles in the regulation of blood pressure, body water balance and thirst and control over vasopressin and aldosterone release. Recently local tissue RASs have been identified with regulatory physiological functions and also with pathophysiological processes including fibrosis, inflammation and dysfunctional cell proliferation. There is a strong correlation between organs vulnerable to diabetic–induced hyperglycemic injury (eg. kidney and retina) and the over activation of local RASs. Increased angiotensin II concentrations in these tissues promotes hypertension and end-organ damage in at least two ways: 1) By activating AT1 receptor proteins thus inducing changes in local blood flow and tissue hydration and 2) Exacerbating hyperglycemic-induced oxidative stress, elevated polyol and hexosamine pathway variability and facilitating glycation end-products. Thus, inhibition of the RAS has become an important treatment approach to control diabetic related hypertension, nephropathy and to a lesser extent retinopathy. The present review emphasizes the recently established importance of the hepatocyte growth factor (HGF)/c-Met receptor system interacting with the RAS in Type 2 diabetes and their likely contribution to end-organ damage. A hypothesis is offered concerning how the pancreatic RAS may affect dimerization of HGF and in turn activation of the c-Met receptor to promote β cell proliferation and insulin synthesis. We conclude with details concerning the development of an AngIV-based small molecule HGF mimetic designed to act as an insulinotropic factor.

Incremento en la expresión del ARNm del receptor c-Met en el cáncer gástrico / Increased expression of the c-Met receptor mRNA in gastric cancer

El cáncer gástrico es una de las patologías malignas más frecuentes en el mundo. En las últimas décadas la atención se ha centrado en posibles alteraciones de factores genéticos que incluyen la activación de proto-oncogenes y/o la inactivación de genes supresores tumorales. El producto del C-MET proto-oncogen y su ligando, el factor de crecimiento del hepatocito (HGF), han sido implicados en la proliferación y migración celular en el cáncer gástrico. En este estudio se analizó a nivel molecular la amplificación del ARNm del receptor c-Met a partir del tejido tumoral gástrico de pacientes a quienes se les practicó gastrectomías, utilizando el método del ácido guanidina-tiocianato-fenol-cloroformo, y el método semicuantitativo de la Reacción en Cadena de la Polimerasa con Transcriptasa Reversa (RT-PCR), encontrándose que los elevados niveles del ARNm del receptor c-Met en las muestras tumorales de los pacientes están relacionados con mayor invasión en la profundidad de la pared gástrica (r = 0,762, p<0,01), incremento en la metástasis a los ganglios linfáticos (r = 0,766, p<0,01), alta frecuencia en tumores pocos diferenciados o indiferenciados (r = 0,912, p<0,001), aumento en el estadiaje del cáncer gástrico (r = 0,838, p<0,001), y en la sobreexpresión por el método inmunohistoquímico (IHQ) de la estreptavidina-biotina marcada de su receptor a nivel proteico (r = 0,858, p<0,001). La amplificación del ARNm y/o la sobreexpresión a nivel proteico del receptor c-Met, pudieran ser utilizados como factores pronósticos en el cáncer gástrico.

Gastric cancer is one of the most common malignancies in the world. In the last decades, the attention has been focused in possible alterations of genetic factors that include proto-oncogene activation and/or the tumor suppressor gene inactivation. The product of the proto-oncogene c-MET and its ligand, hepatocyte growth factor (HGF), have been implicated in cell proliferation and migration in gastric cancer. In this study we analyzed at the molecular level, the amplification of c-Met receptor mRNA from gastric tumor tissue of patients who underwent gastrectomy, using the acid guanidinium-thiocyanate-phenol-chloroform method and the semiquantitative Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) method. It was found that high levels of c-Met receptor mRNA in tumor samples from patients are associated with greater depth of invasion in the gastric wall (r = 0.762, p<0.01), increase in metastases to lymph nodes (r = 0.766, p<0.01), high frequency of poorly differentiated or undifferentiated tumors (r = 0.912, p<0.001), increase in the gastric cancer staging (r = 0.838, p<0.001), and the overexpression, by the immunohistochemistry method (IHC) of the labeled streptavidin-biotin, of the c-Met receptor at the protein level (r = 0.858, p<0.001). The amplification of mRNA and/or protein level overexpression of the c-Met receptor could be used as prognostic factors in gastric cancer.

A STUDY ON RELATIONSHIP BETWEEN HEPATOCYTE GROWTH FACTOR AND EXPRESSION OF ITS C-MET RECEPTOR AND POSTOPERATIVE RECURRENCE OF SMALL HEPATOCELLULAR CARCINOMA / 解放军医学杂志

Objective To investigate the possible relationship between the changes in the serum level of hepatocyte growth factor (HGF) and the tumor c-Met expression in postoperative patients with small primary hepatocellular carcinoma (SHCC) and the recurrence of the cancer. Methods We examinated the HGF concentration in serum by ELISA within 1 day before and 3 days after operative removal of the tumor, and also determined the expression of c-Met protein in the tumor and non-tumor tissue by Western and Northern blotting in situ. Results The serum HGF concentration 1-day before or 3-days after operation was 0.64?0.15ng/ml and 1.41?0.28ng/ml, respectively. There was statistically significant difference between them (P