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

采用免疫组化方法对102例接受UFT联合放疗的OSCC患者活检标本中Jab1的表达进行了研究。我们还分析了每种表达与临床病理特征和患者生存的关系。Jab1表达与宫颈淋巴结转移（p=0.0004）、疾病分期（p=0.0011）、治疗效果（p=0.0133）和患者转归（p=0.0095）有显著相关性。经log-rank检验，Jab1高、低表达肿瘤的5年生存率分别为53.0%、80.6%，差异有统计学意义（p=0.0053）。多因素分析显示，Jab1高水平表达与期生存率降低有关（p=0.0082）。这些结果表明，Jab1可能是UFT联合放射治疗的OSCC患者的一个有用的预后因素。蛋白酶体抑制剂1 （PSI1, 10 ng-100 μg/ml）通过抑制p27^<Kip1>蛋白的降解，对OSCC细胞产生生长抑制作用。此外，PSI1可通过激活caspase-8、caspase-9和caspase-3诱导细胞凋亡，并可通过诱导Beclin-1和微管相关蛋白1轻链3 （LC3）诱导细胞自噬。此外，PSI1能增强5-FU和CDDP的体外抗癌作用，但不能增强TXT的体外抗癌作用。此外，PSI1 （0.1 ~ 1mg/kg/day）可通过抑制p27^<Kip1>蛋白的降解对裸鼠肿瘤发挥抗肿瘤作用，PSI可增强5-FU、TS-1和CDDP的抗肿瘤作用，而TXT在体内不起作用。这些结果表明PSI1可以通过抑制p27^<Kip1>蛋白的降解来发挥抗肿瘤作用，我们可以开发针对口腔鳞状细胞癌中p27^<Kip1>蛋白稳定性的分子靶向治疗。

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.