Association of Fas Related Apoptosis Pathway Genes with the Risk and Prognosis for Oral Cancer

• Main Authors: Chih-Pei Sun, 孫芝佩
• Other Authors: Luo-Ping Ger
• Format: Others
• Language: en_US
• Published: 2006
• Online Access: http://ndltd.ncl.edu.tw/handle/01116308003946601823

碩士 === 國立中山大學 === 生物醫學科學研究所 === 94 === One of the physiological functions of apoptosis is to eliminate cells that have sustained genetic aberrations, thereby preventing damaged cell from attaining uncontrolled cell proliferation or transformation into carcinoma. The apoptotic response is mediated by many apoptotic genes including Fas, survivin, caspases etc. through either the extrinsic pathway (death receptor pathway) or the intrinsic pathway (mitochondrial pathway). In this dissertation, we carried out a hospital-based case-control study to investigate the association between seven Fas related apoptosis pathway genes (Fas, FasL, survivin, XIAP, caspase-3, caspase-8 and caspase-9) and the risk for oral squamous cell carcinoma (OSCC). In this study, 279 newly diagnosed OSCC patients and 469 frequency-matched controls were recruited at Kaohsiung Veterans General Hospital from 2003 to 2006. Total eight various polymorphisms in seven genes mentioned above were examined by PCR-RFLP and our results showed that only FasL –844TT genotype (P=0.047) was associated with the risk of OSCC. However, a trend of increased risk of OSCC was found in people with the increasing putative high-risk genotypes of Fas related apoptosis pathway genes (P for linear trend, 0.034). From our results of the gene-environment interaction analyses, three important observations were listed below: (1) the polymorphism of both FasL T-844C and survivin codon Lys129Glu were risk factors for Fukienese (P=0.023 and P=0.014, respectively), but not for other ethnicities examined. (2) For non-smokers, survivin codon Lys129Glu and caspase-3 A21926C polymorphisms had significant protect (P=0.047 and P=0.024, respectively). (3) For betel quid (BQ) chewers, caspase-9 codon Arg221Gln polymorphism was an important risk factor (P=0.048). Together, the results suggested that gene polymorphisms of Fas related apoptosis pathway were associated with the risk of OSCC. In order to evaluate the relationship between p53 and caspase-3 protein expression levels or clinicopathologic characteristics and survival outcome in OSCC, we examined the protein expression profilings of caspase-3 and p53 in those patients with buccal mucosa squamous cell carcinoma (BMSCC). Total 117 primary buccal carcinoma specimens were collected at KSVGH between 1990 and 2005 and their paraffin-embedded tissues were sectioned and subjected for immunohistochemistry examination. The overall cumulative survival rate was 62% for 5-years, 39% for 10-years and 18% for 14-years, respectively. Ours results showed that the survival rate of BMSCC was significantly correlated with all clinicopathological characteristics including cell differentiation, pathological stage, tumor size, lymph node metastasis, post-operative RT, post-operative CT and BQ chewing status. Most importantly, the high caspase-3 protein level in cytoplasm was an unfavorable prognostic factor in the univariate or the multivariate analysis. In conclusion, the join effect of genetic polymorphisms of Fas related apoptosis pathway genes and gene-environment combined effect may play important roles in the OSCC risk. In addition, high caspase-3 protein expression in cytoplasm may be used as a prognostic marker for patients with BMSCC.