The role of the DLC genes and their regulatory microRNAs in cell migration.
- The role of microRNAs in intercellular communication within the tumor microenvironment of bone-marrow.
Aberrant migration of plasma cells within bone marrow promotes the development of multiple myeloma (MM) and results mainly in the failure of the bone marrow, and further in other organ damage due to expansion of lesions. Aberrant cell migration correlates with the metastatic capability of the tumor cells. In prostate cancer, metastases in other tissues (like lungs, bone, and liver) and its biological heterogeneity are the limiting factors for successful therapy, and the root cause of cancer-related deaths. Developed prostate cancer is asymptomatic in the majority of cases, which when diagnosed and treated causes life-limiting adverse effects without any patient benefit (such as extension of life.) Only a few cases develop an aggressive form with an increased metastatic potential, thus benefiting from therapy.
My previous research focusing on small RhoGAPs revealed that the DLC genes are important in the regulation of cell migration. The DLC gene family (deleted in liver cancer) encodes three Rho GTPase- activating proteins (DLC-1, DLC-2, and DLC-3) that are expressed in most human tissues under normal conditions. These bona fide tumor suppressor genes are often inactivated by promoter hypermethylation in human cancers, which correlates with repressed gene expression (Song et al. 2006, Ullmannova-Benson et al. 2009). The reintroduction of the DLC gene into tumor cells suppresses tumor cell proliferation, migration, and invasion; induces apoptosis in vitro; and reduces tumor formation and metastases in mice models (Ullmannova-Benson et al. 2009, Durkin et al. 2007, Ullmannova et al. 2007; respectively). DLC-1 itself is a potent tumor suppressor; and moreover, its effect in cell migration is potentiated by its relationship with another key tumor suppressor gene PTEN. DLC-1 interaction with PTEN – a key member of multiple myeloma development – is mediated by the aminoterminal SAM domain. Both proteins are co-localized to focal adhesions at the plasma membrane, which enables their involvement in the protein complex regulating cell migration (Heering et al. 2009).