Associations between proteasomal activator PA28γ and outcome of oral squamous cell carcinoma: Evidence from cohort studies and functional analyses.
Associations between proteasomal activator PA28γ and outcome of oral squamous cell carcinoma: Evidence from cohort studies and functional analyses.
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蛋白酶体激活剂 PA28γ 与口腔鳞状细胞癌结果之间的关联：来自队列研究和功能分析的证据。
DOI：
10.1016/j.ebiom.2015.07.004
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发表时间：
2015-08
期刊：
影响因子：
11.1
通讯作者：
Chen Q
中科院分区：
文献类型：
--
作者：
Li J;Feng X;Sun C;Zeng X;Xie L;Xu H;Li T;Wang R;Xu X;Zhou X;Zhou M;Zhou Y;Dan H;Wang Z;Ji N;Deng P;Liao G;Geng N;Wang Y;Zhang D;Lin Y;Ye L;Liang X;Li L;Luo G;Jiang L;Wang Z;Chen Q
提示PA 28 γ在恶性进展中起一定作用。本文旨在通过队列研究探讨PA 28 γ与口腔鳞状细胞癌（OSCC）预后的关系。采用免疫组化方法检测3个独立队列共368例OSCC患者的PA 28 γ表达水平。使用考克斯比例风险回归模型确定总生存期（OS）的多变量风险比。使用C统计量测量模型区分度。此外，还分析了来自癌症基因组图谱（TCGA）数据集的头颈部鳞状细胞癌（HNSCC）患者的OS。在体外和体内进行功能分析。三项研究中患者的中位随访时间分别为60、52和51个月。368例患者中179例（48.6%）肿瘤组织中PA 28 γ高表达。与低表达相比，PA 28 γ高表达与OS恶化密切相关，相对风险分别为5.14（95%CI，2.51-10.5; P < 0.001）、2.82（95%CI，1.73-4.61; P < 0.001）和3.85（95%CI，1.59-9.37; P = 0.003）。在所有三个队列中，PA 28 γ表达也与无病生存率相关（P < 0.005）。这些结果与TCGA HNSCC数据一致（P < 0.006）。在传统的临床因素中加入PA 28 γ后，对全因死亡率的预测能力明显提高（模型3，C统计值：0.78 VS 0.73，P = 0.016）。在功能分析中，我们发现PA 28 γ沉默在体外显著抑制OSCC细胞的生长、增殖和移动，并减少荷瘤小鼠的肿瘤生长和血管生成。PA 28 γ过表达与口腔鳞癌患者不良预后相关PA 28 γ的异常表达可能与口腔鳞癌的发生发展有关。口腔鳞状细胞癌是最常见的口腔鳞状细胞癌之一，具有较高的致死率。然而，很少有预后指标已应用于临床实践。我们发现PA 28 γ在口腔鳞癌组织中的表达明显高于正常组织。作为来自两个独立研究中心的三个队列和来自TCGA数据集中美国人群的额外验证队列的结果，我们证明PA 28 γ是OSCC死亡风险的良好预测因子。同时，我们也证实了PA 28 γ在口腔鳞癌的发生发展中具有潜在的作用。根据中国三个队列的结果，PA 28 γ蛋白在大部分OSCC患者中过表达PA 28 γ是OSCC的一个预后因素。来自TCGA数据集的美国/非中国队列中PA 28 γ mRNA丰度的分析与中国队列研究PA 28 γ沉默一致，可能影响OSCC的体外和体内肿瘤生物学行为。
PA28γ was suggested to play a role in malignant progression. This paper aimed to investigate the association between PA28γ and the prognosis of oral squamous cell carcinoma (OSCC) in cohort studies. The PA28γ expression level was assessed by immunohistochemistry in a total of 368 OSCC patients from three independent cohorts. The Cox proportional hazards regression model was used to determine multivariate hazard ratios for Overall Survival (OS). Model discrimination was measured using C Statistic. Additionally, OS was analyzed in Head Neck Squamous Cell Carcinoma (HNSCC) patients from The Cancer Genome Atlas (TCGA) data set. Functional analyses were conducted both in-vitro and in-vivo. The median follow-up times of patients in the three studies were 60, 52, and 51 months. High expression of PA28γ was identified in tumors from 179 of 368 patients (48.6%). Compared with low expression, high expression of PA28γ was strongly associated with worse OS, with relative risks of 5.14 (95% CI, 2.51–10.5; P < 0.001), 2.82 (95% CI, 1.73–4.61; P < 0.001), and 3.85 (95% CI, 1.59–9.37; P = 0.003). PA28γ expression was also associated with disease-free survival in all three cohorts (P < 0.005). These findings are consistent with TCGA HNSCC data (P < 0.006). The prediction of all-cause mortality was significantly improved when PA28γ was added to the traditional clinical factors (Model 3, C statistic value: 0.78 VS 0.73, P = 0.016). In functional analyses, we found that PA28γ silencing dramatically inhibited the growth, proliferation and mobility of OSCC cells in vitro and reduced tumor growth and angiogenesis in tumor-bearing mice. PA28γ overexpression is associated with adverse prognosis in patients with OSCC. The aberrant expression of PA28γ may contribute to the pathogenesis and progression of OSCC. OSCC is one of the most common HNSCC, which have a high lethally rate. However, few prognostic markers have been applied in the clinical practice. We found that PA28γ in OSCC tumor tissues were significantly high expression than those in normal tissues. As the results of the three cohorts from two independent research centers and from an additional validation cohort from a US population in the TCGA dataset, we demonstrate PA28γ is a good predictor of the risk of death in OSCC. Meanwhile, we demonstrate PA28γ have a potential role in OSCC tumorigenesis. PA28γ protein over-expressed in a large subset of patients with OSCC PA28γ was a prognostic factor in OSCC based on the results of three cohorts in China The analysis of PA28γ mRNA abundance in a US/non-Chinese cohort from TCGA dataset consistent with Chinese-cohort study PA28γ silencing could affect the tumor biological behavior of OSCC both in vitro and vivo.