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INTRACELLULAR SIGNALING IN GASTRIC AND ESOPHAGEAL ADENOCARCINOMA
(GECS – PNCDI2 41-036)

Funding: Romanian Ministry of Education and Research
- (september 2007 – september 2010)

CONSORTIUM:

CO - Stefan S. Nicolau Institute of Virology, 285 Mihai Bravu Ave, sector 3, code 030304, Bucharest, Romania; tel/fax: 004 021 3242590; www.virology.ro.
Principal investigator: Mihaela CHIVU, PhD; e-mail: mihaela.chivu@virology.ro
P1 – Floreasca Emergency Clinical Hospital, Calea Floreasca 8, sector 2, code 014461, Bucharest, Romania; tel: 599.23.00, fax 5992272 / 599238; www.urgentafloreasca.ro
Contacts: Gabriel CONSTANTINESCU, MD, PhD, e-mail: gaconst@zappmobile.ro; Adriana DUMITRU, MD, e-mail: adridumitru@gmail.com
P2 - Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, 258 Fundeni, sector 2, code 022328, Bucharest, Romania; tel/fax: 004 021 3188811; www.icfundeni.ro
Contacts: Prof. Irinel POPESCU, MD, PhD, Simona Olimpia DIMA, MD, PhD; e-mail: dima.simona@gmail.com

ABSTRACT
In the last 50 years, the gastric carcinoma prognostic methods have encountered little progression. 5 year survival rates in patients suffering of gastric carcinoma is 5-15%. For esophageal carcinoma more than 90% cases are, at diagnostic moment, surgically incurable tumors. Their hope for life from the moment when esophageal carcinoma has been diagnosed is 12 – 24 months.
In the last decade, the scientific international community has achieved a better understanding of molecular events leading to solid or hematological tumors, by identifying mutations in cytokine receptors and in regulatory proteins of intracellular signaling. Many studies appeared recently, claim that modifications in intracellular signaling pathways are a possible cause for gastric epithelium hyperplasia [Jenkins BJ-2005]. Research studies concerning this subject showed that Y757F mutation in gp130 co-receptor blocks SOCS3 proteins binding and hamper the signaling pathway inhibition. Same mutation lowers the signal intensity on SHP2 pathway (Src homology 2 proteins)/Erk leading to a diminished expression of the targeted genes, including stomach tumor-suppressor-gene Tff1 which controls cell cycle and differentiation in gastric epithelium.
This project wants to perform a genetic study concerning gastric and esophageal carcinoma etiology, by exploring gp130 co-receptor and Jak1, STAT3 signaling pathways. Putting the light spot on the genetic alterations involved in neoplastic transformation can help in developing new methods for prevention, diagnostic and treatment for gastric adenocarcinoma.
The practical bases for this study consist in collecting DNA and RNA samples from tumor tissue and adjacent normal tissue biopsies from patients with gastric and esophageal adenocarcinoma. These samples will be processed for genetic investigations. Modern genomics and proteomics techniques (PCR quantitative, sequencing, microarray and western blo) will make possible the molecular investigations for the identification of fundamental genetic alterations and the pattern of genetic expression in order to help diagnosis and therapy.
The identification of new biomarkers, will give the possibility to establish new immunohistochemical techniques, and will guide the attitude and the therapeutical strategy. Results will have social benefits and social impact, by reducing sufferance and health costs for chronic patients, and will have a large applicability in primary disease prevention.

Diagram of project execution

Phase I - Patient enrollment and biological resources establishment

Phase II – Establishing serology and microarray protocols for gastric and esophageal adenocarcinoma investigation

Phase III – Identification of candidate genes for biomarkers, and key genes involved in gastric / esophageal epithelium transformation.

Phase IV – Microarray results analysis and confirmation of biomarker candidate gene through complementary molecular biology tests.

Phase V – Testing the concept of screening diagnostic

Phase VI – Final conclusions on gene expression pattern in digestive cancers and dissemination of these conclusions in scientific manifestations.

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