Functional Characterization of the Putative Metastases Suppressor Protein RAI2

The onset of the metastatic cascade -the main cause of cancer-related death is the dissemination of single tumor cells into distant organs. The presence of disseminated tumor cells (DTCs) in the bone marrow (BM) of cancer patients is an independent prognostic factor for the occurrence of metastatic relapse in different epithelial tumors.

In the preceding funding period we were able to identify genes in breast, colon and lung cancer patients, which were associated with DTC status. One of the identified candidate genes is the putative metastasis suppressor gene retinoid acid induced gene 2 (RAI2) with largely unknown molecular function. RAI2 was found to be significantly down regulated in primary tumors of BM-positive patients. Additionally low RAI2 expression was correlated with a significant decreased survival of breast, lung and ovarian cancer patients. Subsequent cell culture-based functional analyses and bioinformatical analyses revealed that up-regulation of the RAI2 transcript is associated with the induction and/or regulation of senescence. Thus, our current results imply that deficient senescence in the primary tumor sustains the dissemination of tumor cells. We assume that the deregulation of RAI2 protein expression might also be important for metastatic outgrowth or escape from dormancy.

The primary goal of the applied project is a comprehensive functional characterization of the RAI2 gene product in the context of tumor cell dissemination. Furthermore we want to investigate whether RAI2 could present a target for the development of future therapeutic strategies for the treatment of cancer patients, e.g. dormancy control.