Zhang Weijing, He Weiling, Shi Yongjie, Zhao Jing, Liu Sailan, Zhang Fengxiang, Yang Jiarui, Xie Chuanmiao, Zhang Yanna
Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.
Department of Gastrointestinopancreatic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
Int J Oncol. 2017 Jan;50(1):173-184. doi: 10.3892/ijo.2016.3784. Epub 2016 Nov 29.
TIMELESS is a highly conserved protein required for the maintenance of normal mammalian circadian oscillations and for controlling cellular metabolism and proliferation. Recently, TIMELESS was implicated in the tumorigenesis of certain cancers. However, little is known on TIMELESS protein expression and its potential as a prognostic factor in cervical cancer. Here, we investigate TIMELESS expression pattern and its clinicopathological significance in early-stage cervical carcinoma. TIMELESS mRNA and protein expression was evaluated by real-time PCR and western blot analysis in cervical cancer cell lines, a normal cervical cell line, as well as in six pairs of surgically removed cervical cancer and adjacent normal cervical tissues. A total of 189 paraffin-embedded cervical carcinoma specimens were detected and diagnosed by immunohistochemistry (IHC), and the clinical significance of TIMELESS expression was further analyzed. Aberrant TIMELESS mRNA and protein expression were demonstrated in cervical cancer cell lines compared with the normal cervical cell line. TIMELESS mRNA and protein expression were significantly increased in cervical cancer specimens compared with adjacent non-cancerous cervical specimens. TIMELESS protein expression was significantly associated with the age (P=0.011), clinical stage (P<0.001), pelvic lymph node metastasis (P<0.001), squamous cell carcinoma antigen (P=0.003), tumor recurrence (P=0.015), vital status (P<0.001), tumor differentiation grade (P<0.001), property of the surgical margin (P=0.036) and lymphovascular space involvement (P=0.001). Patients with increased TIMELESS protein expression showed strong tendencies to receive postoperative radiotherapy (P=0.002). Upregulation of TIMELESS correlated with poorer overall survival (OS) and disease-free survival (DFS). Univariate and multivariate Cox-regression analyses showed that TIMELESS can be regarded as an independent predictive biomarker for poor clinical outcome for early-stage cervical carcinoma. Our results show that TIMELESS overexpression correlates with pelvic lymph node metastasis, lymphovascular space involvement, as well as unfavorable OS and DFS in human cervical cancer. Therefore, TIMELESS expression may be a potential prognostic biomarker for cervical cancer patients.
TIMELESS是一种高度保守的蛋白质,对于维持正常的哺乳动物昼夜节律振荡以及控制细胞代谢和增殖至关重要。最近,TIMELESS与某些癌症的肿瘤发生有关。然而,关于TIMELESS蛋白表达及其在宫颈癌中作为预后因素的潜力知之甚少。在此,我们研究TIMELESS在早期宫颈癌中的表达模式及其临床病理意义。通过实时PCR和蛋白质印迹分析评估了宫颈癌细胞系、正常宫颈细胞系以及六对手术切除的宫颈癌和相邻正常宫颈组织中TIMELESS mRNA和蛋白的表达。通过免疫组织化学(IHC)检测并诊断了总共189例石蜡包埋的宫颈癌标本,并进一步分析了TIMELESS表达的临床意义。与正常宫颈细胞系相比,宫颈癌细胞系中出现了异常的TIMELESS mRNA和蛋白表达。与相邻的非癌性宫颈标本相比,宫颈癌标本中TIMELESS mRNA和蛋白表达显著增加。TIMELESS蛋白表达与年龄(P = 0.011)、临床分期(P < 0.001)、盆腔淋巴结转移(P < 0.001)、鳞状细胞癌抗原(P = 0.003)、肿瘤复发(P = 0.015)、生存状态(P < 0.001)、肿瘤分化程度(P < 0.001)、手术切缘性质(P = 0.036)和脉管间隙浸润(P = 0.001)显著相关。TIMELESS蛋白表达增加的患者接受术后放疗的倾向较强(P = 0.002)。TIMELESS的上调与较差的总生存期(OS)和无病生存期(DFS)相关。单因素和多因素Cox回归分析表明,TIMELESS可被视为早期宫颈癌临床结局不良的独立预测生物标志物。我们的结果表明,TIMELESS过表达与人类宫颈癌的盆腔淋巴结转移、脉管间隙浸润以及不良的OS和DFS相关。因此,TIMELESS表达可能是宫颈癌患者的潜在预后生物标志物。