Received:10.10.2011 Accepted: 15.01.2012 J Gastrointestin Liver Dis March 2012 Vol. 21 No 1, 23-29 Address for correspondence: Carmen C. Diaconu Stefan S Nicolau Institute of Virology 030304, Bucharest, Romania Email: carmen.diaconu@virology.ro IL-6 and IL-11 as Markers for Tumor Aggressiveness and Prognosis in Gastric Adenocarcinoma Patients without Mutations in Gp130 Subunits Laura G. Necula 1 *, Mihaela Chivu-Economescu 1 *, Elena L. Stanciulescu 2 *, Coralia Bleotu 1 , Simona O. Dima 3 , Irina Alexiu 1 , Adriana Dumitru 2 , Gabriel Constantinescu 2 , Irinel Popescu 3 , Carmen C. Diaconu 1 1) Stefan S. Nicolau Institute of Virology; 2) Floreasca Emergency Hospital; 3) Center of Digestive Disease and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania Abstract Background & Aims. A point mutation (gp130Y757F/ Y759F) was identified as being responsible for aberrant activation of gp130 in mice and associated with gastric adenocarcinoma induction. As a result, we investigated the possible role of key point mutations in Tyr from IL6ST exon 17 that encode for the catalytic domain of gp130, and of its respective activators (IL-6 family member cytokines) in human gastric cancer initiation and development. Method. DNA, protein and plasma from 51 patients with gastric adenocarcinoma have been used in exploring gp130 status. We used sequencing analysis of IL6ST exon 17 in order to identify possible mutations that would lead to constitutive active forms of the receptor. The levels of gp130 activators (IL-6, IL-11, LIF) were analyzed by ELISA in plasma and mucosa of patients with gastric adenocarcinoma. Results. Sequencing analysis did not identify mutations in gp130 key positions (Y759, Y767, Y814, Y905 and Y915). An increased IL-6 and IL-11 level in gastric mucosa was observed, correlated with staging, indicating these cytokines as gp130 activators in tumor epithelial cell. Those variations were consistent with increased IL-6 level in plasma. Furthermore, IL-6, but not IL-11 showed a significant correlation with patient’s survival time, suggesting that tissue and plasma concentration of IL-6 might be a marker of tumor aggressiveness with prognostic value. Conclusions. According to our results, no mutations were detected in gp130 key positions in human gastric adenocarcinoma samples. However, gp130 activation may occur due to the increased level of IL-6 and IL-11 cytokines detected that can become valuable biomarkers. *The first three authors equally contributed to this work. Key words gp130 – IL-6 – IL-11– gastric adenocarcinoma – progression. Introduction Gastric cancer is the second most common cause of cancer-related death in the world. Compared with other cancers, morbidity rates are quite high (~700,000/year), making gastric cancer the second most common cause of cancer death worldwide after lung cancer. Furthermore, a substantial proportion of gastric cancer patients who have undergone curative surgery develop recurrent disease [1-3]. Ten-year relative survival varies worldwide between 7.7% and 23.0% and the only therapeutically scheme applied consists of combined chemo-radiation therapy followed by surgical resection. Therefore, the identification of potential molecular markers as new targets for gastric adenocarcinoma therapy may be useful [4, 5]. Although the molecular mechanisms involved in development of gastric cancer are still unclear, the chronic inflammation triggered by the Gram-negative bacterium Helicobacter pylori, which colonizes the epithelium of the gastric mucosa is an important factor in this pathogenesis. Many studies show that Helicobacter pylori infection could double the risk of gastric cancer. Accumulation of (epi-) genetic alterations in p53, tff, E-cadherin, Cox2, and genes encoding components of the TGF-β/Smad signaling cascade are also linked to gastric cancer [6-9]. More recent studies showed that persistent activation of the latent STAT3 promotes the growth and survival of gastric cells and is associated with increased gastric angiogenesis. This protein has the capacity to induce expression of genes that promote angiogenesis (e.g., VEGF), cell-cycle progression (e.g., cyclin D1), and cell survival (e.g., Bcl-xL, survivin) and could be a prognostic factor for poor survival of gastric cancer patients [10, 11]. In the last decade, the international scientific community has achieved a better understanding of the molecular events leading to tumorigenesis, by identifying mutations in