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

应用免疫组织化学方法检测102例口腔鳞癌患者超分割放疗后活检组织中Jab1的表达。还分析了每种表达与临床病理特征和患者生存的关系。JAP1的表达与颈淋巴转移(p=0.0004)、疾病分期(p=0.0011)、疗效(p=0.0133)和患者预后(p=0.0095)显著相关。JAP1高表达和低表达的5年生存率分别为53.0%和80.6%，经对数等级检验，差异有统计学意义(P=0.0053)。多因素分析显示，生存期缩短与JAB1的高表达有关(p=0.0082)。蛋白酶体抑制因子1(10 ng-100μg/ml)可通过抑制p27、kip1、kip1蛋白的降解而抑制口腔鳞癌细胞的生长。此外，PSI1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(LC3)诱导自噬。PSI1在体外可增强5-FU和CDDP的抗癌作用，但不能增强TXT的抗癌作用。此外，PSI1(0.1~1 mg/kg/d)可通过抑制p27；Kip1&gt；蛋白的降解而发挥抗肿瘤作用，PSI可增强5-FU、TS-1和CDDP的体内抗肿瘤作用，但不能增强TXT的体内抗肿瘤作用。这些结果表明，PSI1可能通过抑制p27；；kip1&gt；蛋白的降解而发挥抗肿瘤作用，我们可能开发针对口腔鳞癌p27；；kip1&gt；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.