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Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma
Masanori Hisaoka1, Atsuko Tanaka, Hiroshi Hashimoto
1Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Abstract:
h-warts/LATS1 is a human homolog of the Drosophila warts tumor suppressor gene, which functions as a component of the mitotic apparatus. LATS1-deficient (Lats1(-/-)) mice have been reported to develop ovarian stromal tumors and soft tissue sarcomas. We investigated the status of the h-warts/LATS1 in 50 human soft tissue sarcomas to address its potential function as a tumor suppressor in human sarcoma development. In our RT-PCR assay, 7 (14%) (3 of 4 myxoid liposarcomas, 3 of 7 leiomyosarcomas, 1 of 9 malignant fibrous histiocytomas) of 50 sarcomas examined had no or a reduced expression of the h-warts/LATS1, indicating down-regulated gene expression. We further analyzed alterations of the h-warts/LATS1 in these seven sarcomas. Using microsatellite markers for chromosome 6q23-25.1, to which the h-warts/LATS1 is localized, an allelic loss of this locus was detected in one leiomyosarcoma, in which a missense point mutation of the h-warts/LATS1 was detected by PCR single-strand conformation polymorphism. Clusters of CpG dinucleotides in a 5' putative promoter region were hypermethylated in the other six sarcomas. Our data suggest that the molecular alterations of the h-warts/LATS1 could be of pathologic importance in human sarcomagenesis.
Insights
The human warts/LATS1 gene, a tumor suppressor, showed reduced expression in 14% of soft tissue sarcomas. Molecular alterations, including gene deletion and promoter hypermethylation, suggest its role in human sarcoma development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The h-warts/LATS1 gene is a human homolog of the Drosophila warts tumor suppressor gene.
- LATS1-deficient mice develop ovarian stromal tumors and soft tissue sarcomas, suggesting a tumor suppressor role.
- Investigating h-warts/LATS1 in human sarcomas is crucial for understanding sarcoma development.
Purpose of the Study:
- To investigate the status of h-warts/LATS1 in human soft tissue sarcomas.
- To determine if h-warts/LATS1 functions as a tumor suppressor in human sarcoma development.
- To identify molecular alterations affecting h-warts/LATS1 expression in sarcomas.
Main Methods:
- Reverse transcription polymerase chain reaction (RT-PCR) was used to assess h-warts/LATS1 expression levels.
- Microsatellite markers were employed to detect allelic loss on chromosome 6q23-25.1.
- PCR single-strand conformation polymorphism (PCR-SSCP) and methylation-specific PCR were used to analyze gene mutations and promoter methylation.
Main Results:
- Reduced or absent h-warts/LATS1 expression was observed in 7 (14%) of 50 human soft tissue sarcomas.
- Specific sarcoma subtypes, including myxoid liposarcomas, leiomyosarcomas, and malignant fibrous histiocytomas, showed down-regulated gene expression.
- Molecular alterations identified included allelic loss, a missense point mutation, and hypermethylation of the 5' promoter region of h-warts/LATS1.
Conclusions:
- Molecular alterations of h-warts/LATS1, such as down-regulated expression and genetic changes, are implicated in human soft tissue sarcomagenesis.
- These findings highlight the potential role of h-warts/LATS1 as a tumor suppressor in the development of human sarcomas.
- Further research into h-warts/LATS1 alterations may provide insights into novel therapeutic strategies for soft tissue sarcomas.