Genetic alterations responsible for metastatic phenotypes of lung cancer cells.

It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations in cells. Thus, in order to understand the process of acquisition of metastatic phenotypes in cancer cells, it is indispensable to identify genes whose alterations accumulate during cancer progression and correlate with metastatic phenotypes of cancer cells. For this reason, we have been searching for genes that are preferentially altered in metastatic lung cancer cells and have activities to regulate their metastatic potentials. In lung cancer, both the p16INK4A/RB and p53 genes are frequently inactivated and are critical determinants for the regulation of cell growth and apoptosis. However, it still remains unclear whether these genes are also involved in the regulation of metastatic potential in lung cancer cells. Recently, we identified a novel myosin family gene, MYO18B, from the chromosome 22q12.1 region which shows frequent loss of heterozygosity in advanced lung cancer, and we found that this gene is inactivated in approximately 50% of lung cancers by deletions, mutations and methylation. Furthermore, restoration of MYO18B expression suppressed anchorage-independent growth of lung cancer cells. Thus, it was indicated that the MYO18B gene is a strong candidate for a metastasis suppressor gene of human lung cancer. Further functional and biological studies of the MYO18B gene will help us understand the molecular pathway of human lung cancer progression.