Hunter and colleagues have identified a candidate gene, Sipa1, with an amino acid polymorphism that influences metastasis in cancer. Cancer mortality is most often the result of metastasis rather than the primary tumor.Previous studies from Kent Hunter's group demonstrated that the genetic background of the host can influence metastatic efficiency. They expressed the polyoma middle-T transgene in various strains of inbred mice and through quantitative trait genetic mapping showed the presence of a putative metastasis efficiency locus on mouse chromosome 19. This chromosome region, which is orthologous to human 11q12-13, harbors a known metastasis suppressor gene Brms1. However, this gene has no obvious polymorphisms that influence metastasis.
Authors used a multiple cross mapping strategy that uses the shared haplotypes in different inbred strains of mice to reduce the number of candidate genes. This reduced the number of potential genes from 500 to 23, which were then prioritized base d on their known molecular function. After analyzing and discounting several of the genes, the authors found that Sipa1 had a polymorphism that results in an Alanine to threonine substitution in a protein-protein interaction domain known as a PDZ domain.
Sipa1 is a mitogen inducidble gene that encodes a GTPase activating protein (GAP) that negatively regulates RAP1 and RAP2 GTPases. Human SIPA1 has recently been found to interact with the water channel aquaporin 2 (AQP2), by its PDZ domain, so the authors used AQP2 to see if the Alanine to threonine substitution affected this interaction.
Transient transfection assays demonstrated that the FVB allele is less efficient than the DBA allele at reducing the activity of GTP-RAP1. AQP2 inhibits this and does so more effectively with the DBA allele. So, cells expressing the FVB allele will have reduced levels of Rap-GTP activity. Reducing the expression of Sipa1 in cells in vitro indicates that SIPA 1 modulates the adhesive properties of cells, consistent with its effect on RAP 1, which is known to affect cell-cell interactions. A series of experiment has shown that RNA Inhibiton of Sipa1 decreased the numbers of pulmonary metastases from a highly metastatic mammary tumor cell line. Conversely, over expression of the FVB allele increased the numbers of pulmonary metastases. Analysis of human tumors also demonstrated that over expression of SIPA1 is associated with metastatic progression.
The results demonstrate that Sipa1, as determined by its overall protein concentration and/or its availability to inactivate RAP1, modulates metastatic progression. Additional studies are required to verify this and to investigate another potential gene close to Sipa 1 that might also contribute to the Mtes1 locus.
Source: Nature Review Cancer.