Su Liping, Wang Ying, Xiao Mingzhen, Lin Yuan, Yu Lei
Department of Endodontics, College of Stomatology, Fourth Military Medical University, Xi'an, China.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010 Oct;110(4):484-91. doi: 10.1016/j.tripleo.2010.04.009.
Survivin, a key member of the inhibitor of apoptosis protein family, has been reported to be capable of regulating both cellular proliferation and apoptotic cell death. This protein is found to be overexpressed in many human cancers. The aim of this study was to evaluate the prognostic significance of survivin mRNA expression in oral squamous cell carcinoma (OSCC) and to analyze its correlation with chemoresistance. Reverse-transcription polymerase chain reaction assay was performed to detect the expression of survivin mRNA in OSCC cell lines or tissue samples. Immunohistochemistry was performed to detect the expression of survivin protein in OSCC tissues or corresponding nontumor tissues. Then the correlation between survivin mRNA expression and clinicopathologic features or prognosis of OSCC patients was analyzed. Small interfering RNA technology was used to down-regulate the expression of the survivin gene in the OSCC cell line. Methylthiazol tetrazolium and flow cytometric assays were performed to detect proliferation and apoptosis of the OSCC cell line (HSC-3). Furthermore, the effect of small interfering RNA (siRNA) targeting survivin on the sensitivity of OSCC cells to chemotherapeutic agents (cisplatin and 5-fluorouracil [5-FU]) was determined. Results showed that the levels of survivin mRNA expression were significantly higher in OSCC cells or tissues than those in normal human oral keratinocyte or corresponding noncancerous tissues. The immunostaining of survivin protein was significantly stronger in OSCC tissues than in corresponding nontumor tissues. Moreover, high survivin mRNA expression was correlated with poorer tumor differentiation, higher clinical stage, and the presence of lymph node metastasis (P < .05). Multivariate analysis showed that the status of survivin mRNA could be an independent prognostic factor for OSCC patients (hazard ratio 2.71, 95% confidence interval 1.46-5.10; P = .012). In addition, siRNA-mediated survivin down-regulation could significantly inhibit proliferation and induce apoptosis of OSCC cells. Suvivin down-regulation could also significantly enhance chemosensitivity of OSCC cells, which was associated with apoptosis enhancement. Thus, the status of survivin mRNA expression was a potential prognostic factor for OSCC patients, and siRNA-mediated survivin down-regulation could become a novel strategy for chemosensitization of human OSCCs.
生存素是凋亡抑制蛋白家族的关键成员，据报道它能够调节细胞增殖和凋亡性细胞死亡。人们发现这种蛋白在多种人类癌症中过度表达。本研究的目的是评估生存素mRNA表达在口腔鳞状细胞癌（OSCC）中的预后意义，并分析其与化疗耐药性的相关性。采用逆转录聚合酶链反应检测OSCC细胞系或组织样本中生存素mRNA的表达。采用免疫组织化学法检测OSCC组织或相应非肿瘤组织中生存素蛋白的表达。然后分析生存素mRNA表达与OSCC患者临床病理特征或预后的相关性。利用小干扰RNA技术下调OSCC细胞系中生存素基因的表达。采用甲基噻唑四氮唑和流式细胞术检测OSCC细胞系（HSC-3）的增殖和凋亡情况。此外，还确定了靶向生存素的小干扰RNA（siRNA）对OSCC细胞对化疗药物（顺铂和5-氟尿嘧啶[5-FU]）敏感性的影响。结果显示，OSCC细胞或组织中生存素mRNA的表达水平显著高于正常人口腔角质形成细胞或相应的非癌组织。生存素蛋白的免疫染色在OSCC组织中明显强于相应的非肿瘤组织。此外，生存素mRNA高表达与肿瘤分化差、临床分期高和淋巴结转移有关（P<0.05）。多因素分析表明，生存素mRNA状态可能是OSCC患者的独立预后因素（风险比2.71，95%置信区间1.46-5.10；P=0.012）。此外，siRNA介导的生存素下调可显著抑制OSCC细胞的增殖并诱导其凋亡。生存素下调还可显著增强OSCC细胞的化疗敏感性，这与凋亡增强有关。因此，生存素mRNA表达状态是OSCC患者的潜在预后因素，siRNA介导的生存素下调可能成为人类OSCC化疗增敏的新策略。
