Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Biomarkers | Research

An integrative evaluation of circadian gene TIMELESS as a pan-cancer immunological and predictive biomarker

Authors: Yaocheng Yang, Xianzhe Tang, Zhengjun Lin, Tao Zheng, Sheng Zhang, Tang Liu, Xiaolun Yang

Published in: European Journal of Medical Research | Issue 1/2023

Login to get access

Abstract

Background

The gene TIMELESS, which is involved in the circadian clock and the cell cycle, has recently been linked to various human cancers. Nevertheless, the association between TIMELESS expression and the prognosis of individuals afflicted with pan-cancer remains largely unknown.

Objectives

The present study aims to exhaustively scrutinize the expression patterns, functional attributes, prognostic implications, and immunological contributions of TIMELESS across diverse types of human cancer.

Methods

The expression of TIMELESS in normal and malignant tissues was examined, as well as their clinicopathologic and survival data. The characteristics of genetic alteration and molecular subtypes of cancers were also investigated. In addition, the relationship of TIMELESS with immune infiltration, tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity was illustrated. Immunohistochemistry (IHC) was used to validate the expression of TIMELESS in clinical patients with several types of cancer.

Results

In contrast to the matching normal controls, most tumor types were found to often overexpress TIMELESS. Abnormal expression of TIMELESS was significantly related to more advanced tumor stage and poorer prognosis of breast cancer, as well as infiltrating immune cells such as cancer-associated fibroblast infiltration in various tumors. Multiple cancer types exhibited abnormal expression of TIMELESS, which was also highly correlated with MSI and TMB. More crucially, TIMELESS showed promise in predicting the effectiveness of immunotherapy and medication sensitivity in cancer therapy. Moreover, cell cycle, DNA replication, circadian rhythm, and mismatch repair were involved in the functional mechanisms of TIMELESS on carcinogenesis. Furthermore, immunohistochemical results manifested that the TIMELESS expression was abnormal in some cancers.

Conclusions

This study provides new insights into the link between the circadian gene TIMELESS and the development of various malignant tumors. The findings suggest that TIMELESS could be a prospective prognostic and immunological biomarker for pan-cancer.
Appendix
Available only for authorised users
Literature
1.
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.CrossRefPubMed
2.
Kocarnik JM, Compton K, Dean FE, Fu W, Gaw BL, Harvey JD, et al. cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: a systematic analysis for the global burden of disease study 2019. JAMA Oncol. 2022;8:420–44.CrossRefPubMed
3.
Chen LY, Li JT, Chang MM. Cancer diagnosis and disease gene identification via statistical machine learning. Curr Bioinform. 2020;15:956–62.CrossRef
4.
Liu JF, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, et al. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 2018;173:400.CrossRefPubMedPubMedCentral
5.
Mazzoccoli G, Laukkanen MO, Vinciguerra M, Colangelo T, Colantuoni V. A timeless link between circadian patterns and disease. Trends Mol Med. 2016;22:68–81.CrossRefPubMed
6.
Takumi T, Nagamine Y, Miyake S, Matsubara C, Taguchi K, Takekida S, et al. A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1. Genes Cells. 1999;4:67–75.CrossRefPubMed
7.
8.
Unsal-Kaçmaz K, Mullen TE, Kaufmann WK, Sancar A. Coupling of human circadian and cell cycles by the timeless protein. Mol Cell Biol. 2005;25:3109–16.CrossRefPubMedPubMedCentral
9.
Gotter AL, Suppa C, Emanuel BS. Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. J Mol Biol. 2007;366:36–52.CrossRefPubMed
10.
11.
12.
Wang J, Huang Q, Hu X, Zhang S, Jiang Y, Yao G, et al. Disrupting circadian rhythm via the PER1-HK2 axis reverses trastuzumab resistance in gastric cancer. Cancer Res. 2022.
13.
Shafi AA, Knudsen KE. Cancer and the circadian clock. Can Res. 2019;79:3806–14.CrossRef
14.
Ward EM, Germolec D, Kogevinas M, McCormick D, Vermeulen R, Anisimov VN, et al. Carcinogenicity of night shift work. Lancet Oncol. 2019;20:1058–9.CrossRef
15.
16.
Dun A, Zhao X, Jin X, Wei T, Gao X, Wang Y, et al. Association between night-shift work and cancer risk: updated systematic review and meta-analysis. Front Oncol. 2020;10:1006.CrossRefPubMedPubMedCentral
17.
18.
19.
Xian H, Li Y, Zou B, Chen Y, Yin H, Li X, et al. Identification of TIMELESS and RORA as key clock molecules of non-small cell lung cancer and the comprehensive analysis. BMC Cancer. 2022;22:107.CrossRefPubMedPubMedCentral
20.
21.
Liu S-L, Lin H-X, Lin C-Y, Sun X-Q, Ye L-P, Qiu F, et al. TIMELESS confers cisplatin resistance in nasopharyngeal carcinoma by activating the Wnt/β-catenin signaling pathway and promoting the epithelial mesenchymal transition. Cancer Lett. 2017;402:117–30.CrossRefPubMed
22.
Wang F, Chen Q. The analysis of deregulated expression of the timeless genes in gliomas. J Canc Res Ther. 2018;14:S708–12.CrossRef
23.
Tozlu-Kara S, Roux V, Andrieu C, Vendrell J, Vacher S, Lazar V, et al. Oligonucleotide microarray analysis of estrogen receptor alpha-positive postmenopausal breast carcinomas: identification of HRPAP20 and TIMELESS as outstanding candidate markers to predict the response to tamoxifen. J Mol Endocrinol. 2007;39:305–18.CrossRefPubMed
24.
Wu C, Jin X, Tsueng G, Afrasiabi C, Su AI. BioGPS: building your own mash-up of gene annotations and expression profiles. Nucleic Acids Res. 2016;44:D313–6.CrossRefPubMed
25.
Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019;30:44–56.CrossRefPubMed
26.
27.
Zack TI, Schumacher SE, Carter SL, Cherniack AD, Saksena G, Tabak B, et al. Pan-cancer patterns of somatic copy number alteration. Nat Genet. 2013;45:1134–40.CrossRefPubMedPubMedCentral
28.
Priestley P, Baber J, Lolkema MP, Steeghs N, de Bruijn E, Shale C, et al. Pan-cancer whole-genome analyses of metastatic solid tumours. Nature. 2019;575:210–6.CrossRefPubMedPubMedCentral
29.
Saghafinia S, Mina M, Riggi N, Hanahan D, Ciriello G. Pan-cancer landscape of aberrant DNA Methylation across human tumors. Cell Rep. 2018;25:1066-80.e8.CrossRefPubMed
30.
Vosshall LB, Price JL, Sehgal A, Saez L, Young MW. Block in nuclear localization of period protein by a second clock mutation, timeless. Science (New York, NY). 1994;263:1606–9.CrossRef
31.
32.
33.
Patke A, Young MW, Axelrod S. Molecular mechanisms and physiological importance of circadian rhythms. Nat Rev Mol Cell Biol. 2020;21:67–84.CrossRefPubMed
34.
Barrio-Alonso E, Lituma PJ, Notaras MJ, Albero R, Bouchekioua Y, Wayland N, et al. Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling. Cell Rep. 2023;42: 112375.CrossRefPubMedPubMedCentral
35.
Zhang W, He W, Shi Y, Zhao J, Liu S, Zhang F, et al. Aberrant TIMELESS expression is associated with poor clinical survival and lymph node metastasis in early-stage cervical carcinoma. Int J Oncol. 2017;50:173–84.CrossRefPubMed
36.
37.
Desbois M, Wang Y. Cancer-associated fibroblasts: key players in shaping the tumor immune microenvironment. Immunol Rev. 2021;302:241–58.CrossRefPubMed
38.
Ascione CM, Napolitano F, Esposito D, Servetto A, Belli S, Santaniello A, et al. Role of FGFR3 in bladder cancer: treatment landscape and future challenges. Cancer Treat Rev. 2023;115: 102530.CrossRefPubMed
39.
Wang C, Lutes LK, Barnoud C, Scheiermann C. The circadian immune system. Sci Immunol. 2022;7: e465.CrossRef
40.
41.
42.
Gotter AL. Tipin, a novel timeless-interacting protein, is developmentally co-expressed with timeless and disrupts its self-association. J Mol Biol. 2003;331:167–76.CrossRefPubMed
43.
Li Z, Stuart RO, Qiao J, Pavlova A, Bush KT, Pohl M, et al. A role for Timeless in epithelial morphogenesis during kidney development. Proc Natl Acad Sci U S A. 2000;97:10038–43.CrossRefPubMedPubMedCentral
44.
Murakami H, Keeney S. Temporospatial coordination of meiotic DNA replication and recombination via DDK recruitment to replisomes. Cell. 2014;158:861–73.CrossRefPubMedPubMedCentral
45.
Schalbetter SA, Mansoubi S, Chambers AL, Downs JA, Baxter J. Fork rotation and DNA precatenation are restricted during DNA replication to prevent chromosomal instability. Proc Natl Acad Sci U S A. 2015;112:E4565–70.CrossRefPubMedPubMedCentral
46.
47.
Zou X, Zhu C, Zhang L, Zhang Y, Fu F, Chen Y, et al. MicroRNA-708 suppresses cell proliferation and enhances chemosensitivity of cervical cancer cells to cDDP by negatively targeting timeless. Onco Targets Ther. 2020;13:225–35.CrossRefPubMedPubMedCentral
48.
Shen X, Li M, Mao Z, Yu W. Loss of circadian protein TIMELESS accelerates the progression of cellular senescence. Biochem Biophys Res Commun. 2018;503:2784–91.CrossRefPubMed
Metadata
Title
An integrative evaluation of circadian gene TIMELESS as a pan-cancer immunological and predictive biomarker
Authors
Yaocheng Yang
Xianzhe Tang
Zhengjun Lin
Tao Zheng
Sheng Zhang
Tang Liu
Xiaolun Yang
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01519-3

Other articles of this Issue 1/2023

European Journal of Medical Research 1/2023 Go to the issue

Research

Effects of metformin therapy on HMGB1 levels in rheumatoid arthritis patients

Research

Integrated investigation of the clinical implications and targeted landscape for RNA methylation modifications in hepatocellular carcinoma

Correspondence

Reassessing the Casual Effects of Genetically Predicted Obesity on Pelvic Organ Prolapse: Letter to the Editor on “Lifestyle factors, metabolic factors and socioeconomic status for pelvic organ prolapse: a Mendelian randomization study”

Research

Identifying individualized prognostic signature and unraveling the molecular mechanism of recurrence in early-onset colorectal cancer

Research

The prognostic role of γδ T cells in colorectal cancer based on nomogram

Research

Predictors of neurologic outcomes and mortality in physically abused and unintentionally injured children: a retrospective observation study