DLC1 in inflammation-driven gastric carcinogenesis

• Applicant: Privatdozentin Dr. Elke Burgermeister
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: from 2009 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 72476416

Caveolin-1 (Cav1) is a scaffold protein and pathogen receptor in the plasma membrane which organizes signaling molecules to control epithelial integrity and cell fate decisions such as proliferation and survival. We showed in BU2285/1-2 that Cav1 is present in the normal human and murine stomach, where it acts as a coactivator of the differentiation-promoting nuclear receptor PPARgamma. Cav1 and pharmacological activation of PPARgamma inhibited growth of gastric cancer (GC) cells in vitro and in vivo. Cav1 was down-regulated in patients with primary GC, and in mice and cell lines infected with Helicobacter pylori (HP), a major risk factor for GC in humans, resulting in loss of its tumor suppressor functions. Cav1 knockout mice showed an enhanced susceptibility against HP-related gastritis and tissue damage, and Cav1 protected human gastric epithelial cells against HPs oncogenic virulence factor CagA by recruiting deleted in liver cancer-1 (DLC1), a regulator of small GTPases and cell-cell/matrix contacts. We identified DLC1 as a novel stomach-specific interaction partner of Cav1 which counteracted HP-induced rearrangements of the cytoskeleton and focal adhesions. Similar to Cav1, DLC1 is a tumor suppressor in normal tissue which is frequently lost in human primary tumors but regained in advanced stage cancer, e.g. during metastasis. In the 3 year extension period, we plan to investigate in depth the function of the Cav1/DLC1 complex. A translational approach of functional molecular studies in human GC cells, an inflammation-driven mouse model of GC and expression/clinical data from GC patients is expected to elaborate the causative role of the Cav1/DLC1 complex in gastric carcinogenesis. Survival prognosis of GC is poor and available treatment options limited. Therefore, our research aims to contribute to the characterisation of DLC1 as a potential novel target in GC or future early diagnostic marker for the transition of HP-induced gastritis to neoplasia.

• DFG Programme: Research Grants
• International Connection: USA
• Participating Person: Professor Dr. Timothy Wang