Development of molecular targeting therapy against stability of p27^<Kip1> protein in oral squamous cell carcinoma.

应用免疫组化方法检测102例接受UFT联合放疗的口腔鳞癌患者活检标本中Jab 1的表达。还分析了每种表达与临床病理特征和患者生存期的关系。Jab 1表达与颈淋巴结转移（p=0.0004）、疾病分期（p=0.0011）、治疗效果（p=0.0133）和患者预后（p=0.0095）之间存在显著相关性。Jab 1高表达和低表达肿瘤的5年生存率分别为53.0%和80.6%，经对数秩检验，该差异具有显著性（p=0.0053）。多变量分析显示，长期生存率降低与高水平的Jab 1表达相关（p=0.0082）。蛋白酶体抑制剂1（PSI 1; 10 ng-100 μg/ml）可通过抑制p27^蛋白的降解而抑制OSCC细胞<Kip1>的生长。另外，PSI 1可通过激活caspase-8、caspase-9和caspase-3诱导细胞凋亡，并可能通过诱导Beclin-1和微管相关蛋白1轻链3（LC 3）诱导自噬。PSI 1能增强5-FU和CDDP的体外抗肿瘤作用，但对TXT无明显增强作用。PSI 1（0.1- 1 mg/kg/d）可通过抑制p27^蛋白的降解而发挥抗肿瘤作用<Kip1>，PSI可增强5-FU、TS-1和CDDP的抗肿瘤作用，但对TXT无明显增强作用，提示PSI 1可通过抑制p27^蛋白的降解而发挥抗肿瘤作用<Kip1>，有望开发针对p27^蛋白稳定性的分子靶向<Kip1>治疗口腔鳞癌。

The Jab1 expression was investigated by immunohistochemistry in biopsy samples from 102 OSCC patients who were treated by UFT in combination with radiation. Associations of each expression with clinicopathological characteristics and patient survival were also analyzed. A significant association was found between Jab1 expression and cervical lymph node metastasis (p=0.0004), stage of disease (p=0.0011), therapeutic effect (p=0.0133) and patient outcome (p=0.0095). The 5-year survival rates of Jab1 high and low expression tumors were 53.0 % and 80.6 %, respectively, and this difference was significant (p=0.0053) by log-rank test. Multivariate analysis revealed that reduced term survival was related to high levels of Jab1 expression (p=0.0082). These results suggest that Jab1 may be a useful prognostic factor in OSCC patients treated by UFT in combination with radiation.Proteasome inhibitor 1 (PSI1; 10 ng-100 μg/ml) could exert growth inhibitory effects on OSCC cells through suppressing the degradation of p27^<Kip1> protein. In addition, PSI1 could induce apoptosis through the activation of caspase-8, caspase-9 and caspase-3, and that might induce autophage through the induction of Beclin-1 and microtuble associated protein 1 light chain 3 (LC3). Moreover, PSI1 could enhance the anticancer effects of 5-FU and CDDP, but not TXT in vitro. Furthermore, PSI1 (0.1-1mg/kg/day) could exert antitumor effects on nude mice tumors through suppressing the degradation of p27^<Kip1> protein, and PSI could enhance the antitumor effects of 5-FU, TS-1 and CDDP, but not TXT in vivo.These results indicate that PSI1 can exert antitumor effects through suppressing the degradation of p27^<Kip1> protein, and we may be able to develop the molecular targeting therapy against stability of p27^<Kip1> protein in oral squamous cell carcinoma.