Overexpressing PTTG1 Induces Senescence in Normal Human Fibroblasts and Its Implication in Early Oral Tumorigenesis

• Main Authors: Yi-Hsin Hsu, 許憶馨
• Other Authors: Jing-Jer Lin
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/41080450294751132910

博士 === 國立陽明大學 === 生物藥學研究所 === 98 === Pituitary tumor transforming gene (PTTG1 or human securin) is involved in cell-cycle control through inhibition of sister-chromatid separation. Elevated levels of PTTG1 were found to be associated with many different tumor types that were shown to be involved in late stage tumor progression. However, the involvement and the role of PTTG1 in initiating tumorigenesis are unknown. Here we overexpress PTTG1 in normal human fibroblasts using an adenoviral delivery system and analyzed for its effects on induction of senescence. Further, the expression levels of PTTG1 were analyzed in pre-cancerous lesions and squamous cell carcinoma samples from oral cavity. We found PTTG1 overexpression in normal human fibroblasts caused chromosome instability, which subsequently induced p53-dependent senescence through activation of DNA-damage response pathway. Moreover, PTTG1 was over-expressed in both precancerous lesions and OSCC. The expression of PTTG1 was associated with carcinogen exposure in vivo and in vitro. PTTG1over-expression was an independent factor for oral cancer development in precancerous lesions. In conclusion, our results provide the first evidence for the involvement of PTTG1 during the early stages of tumor formation. Senescence induced by PTTG1 over-expression is similar to that of oncogene-induced senescence in that it serves as a fail-safe mechanism to protect normal cells from transformation at the early stages of tumorigenesis.