title: Aberrant TIMELESS expression is associated with poor clinical survival and lymph node metastasis in early-stage cervical carcinoma.
abstract: 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.
authors.affiliation: 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.
authors.forename: Weijing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Gastrointestinopancreatic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Weiling
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Clinical Examination, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510260, P.R. China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Sailan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Eight‑year program, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Fengxiang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Eight‑year program, Zhongshan Medical School, Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Chuanmiao
authors.initials: C
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Yanna
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C509769:TIMELESS protein, human