Down-regulation of plakoglobin in soft tissue sarcoma is associated with a higher risk of pulmonary metastasis

Soft tissue sarcomas (STS) behave with aggressiveness and metastatic potential, that can vary depending on their locations. There has been little information on the exact molecular mechanisms involved in their biological aggressiveness. To identify genes involved in the differences, the gene expression profiles were compared between STS-orthotopic and heterotopic implanted models, and their significance in human STS was verified. Human fibrosarcoma HT1080 cells were implanted either in the quadriceps femoris muscles or footpads of nude mice, and the gene expression profiles of the tumors were compared by cDNA arrays. The mRNA and protein levels of the identified genes were examined by both real time RT-PCR and immunohistochemistry not only in the tumors of the models, but also in clinical STS. The implanted HT1080 cells demonstrated different growth and metastatic potentials depending on their implant locations. cDNA array analyses showed decreased expression of the plakoglobin gene in the intramuscle-implanted group, which was statistically confirmed by real-time RT-PCR (p = 0.04). Plakoglobin was immunolocalized diffusely in the cytoplasm of tumor cells implanted in the footpads, but not those in the muscle. Real-time RT-PCR assays of clinical STS showed that the mean plakoglobin/glyceraldehyde 3-phosphate dehydrogenase (G3PDH) ratio in primary sarcoma tissues with pulmonary metastases (0.92) was significantly lower than in those without metastasis (6.58) (p < 0.0001), and that STS cases with high plakoglobin gene expression had an excellent prognosis. These results suggest that plakoglobin gene expression level might be useful as a new biomarker for metastasis and prognosis of human STS.