Gastric adenocarcinoma is the second most common cause of cancer related-death worldwide. Recent estimates indicate 900,000 cases were recorded in 2002 with 700,000 deaths. The relative 5-year survival rates are less than 20%. The World Health Organization has classified H.pylori as class I carcinogen and the main risk factor for gastric cancer. This is of a significant concern in the presence of more than 3 billion people in the world with H. pylori infection. One of the main challenges that face clinicians and patients equally, in the context of gastric cancer, is the fact that infection with H.pylori startsat childhood whereas gastric cancer, when develops, occurs after several decades of chronic infection. Understanding the molecular events that enhance and promote H.pylori mediated carcinogenic effects has significant contribution to our knowledge of the biology of the disease, early diagnosis, and potential preventive and therapeutic strategies of gastric cancer. MicroRNAs (miRNAs) are small (~ 22 nt) non-coding RNAs that regulate target genes at the post-transcription levels. They have been found to regulate oncogene and tumor suppressor signaling pathways. In addition to playing a major role in shaping the molecular signaling in normal and cancerous cells, miRNAs, being stable in blood stream, can offer an excellent opportunity for non-invasive diagnostics and risk assessment in gastric cancer. What is not clear is if specific miRNAs are critical for gastric tumorigenesis. Overexpressed miRNAs can serve as de novo diagnostic or prognostic biomarkers. Moreover, inhibition of selected oncogenic miRNAs or reconstitution of silenced tumor suppressor miRNAs can have a therapeutic impact. However, our lack of knowledge about miRNAs during the development and progression stages of gastric cancer has limited their clinical use in this devastating cancer. Our recent pilot studies have revealed a unique molecular signature for advanced gastric cancer. Based on our preliminary data, we hypothesize: H.pylori-associated gastric cancers have their own unique miRNA signature that contributes to the stages development and progression of gastric cancer. Unveiling this signature is likely to improve our understanding of the biology of gastric cancer and improve our currently limited diagnostic, prognostic and / or therapeutic clinical utilities. To test our hypothesis and, thereby, accomplish the objectives of this proposal, we have developed three specific aims.
In Aim 1, we plan to investigate the role of H.pylori in modulating the miRNA signature during the early stages of gastric tumorigenesis in vivo using the TFF1 knockout mouse model. We also plan to examine the miRNA signature in the early and late stages of gastric cancer (stages I-II and III-IV).
In Aim 2, we will perform integrated analysis of mouse and human data and validate the results in order to identify the miRNA network map in the multi-step stages of development and progression of gastric cancer.
In Aim 3, we will investigate the diagnostic and prognostic potential of miRNAs. We will also examine the potential tumor suppressor functions of the down-regulated miRNAs. Upon completion of our aims, we expect to gain more understanding of the role of H.pylori in shaping the miRNA signature and promoting the multi-step gastric tumorigenesis. Using the powerful technologies and bioinformatics in this proposal, we expect the identification of diagnostic, prognostic and possibly therapeutic miRNA targets in gastric cancer.
Gastric cancer is one of the most prevalent cancers world-wide. In this proposal, we plan to determine the miRNA signature in gastric cancer in order to identify the biological, diagnostic, prognostic, and possibly therapeutic values of miRNAs.