TIMELESS Promotes Tumor Progression by Enhancing Macrophages Recruitment in Ovarian Cancer

Overview

Journal Front Oncol

Specialty Oncology

Date 2021 Sep 7

PMID 34490127

Citations 10

Authors

Xin Xing

Fei Gu

Lanyu Hua

Xiaoxiao Cui

Dongxue Li

Zhiyong Wu

Rong Zhang

Affiliations

Soon will be listed here.

Abstract

Objective: Ovarian cancer (OV) is the most fatal and frequent type of gynecological malignancy worldwide. TIMELESS (TIM), as a circadian clock gene, has been found to be highly expressed and predictive of poor prognosis in various cancers. However, the function of TIM in OV is not known. This study was designed to investigate the biological functions and underlying mechanisms of TIM during OV progression.

Methods: Cell viability assay, cell migration assay, immunohistochemistry staining, qPCR analyses, and tumor xenograft model were used to identify the functions of TIM in OV. Bioinformatics analyses, including GEPIA, cBioPortal, GeneMANIA, and TIMER, were used to analyze the gene expression, genetic alteration, and immune cell infiltration of TIM in OV.

Results: TIM is highly expressed in OV patients. TIM knockdown inhibited OV cell proliferation, migration, and invasion both and . Genetic alteration of TIM was identified in patients with OV. TIM co-expression network indicates that TIM had a wide effect on the immune cell infiltration and activation in OV. Further analysis and experimental verification revealed that TIM was positively correlated with macrophages infiltration in OV.

Conclusions: Our study unveiled a novel function of highly expressed TIM associated with immune cell especially macrophages infiltration in OV. TIM may serve as a potential prognostic biomarker and immunotherapy target for OV patients.

Citing Articles

The Common Hallmarks and Interconnected Pathways of Aging, Circadian Rhythms, and Cancer: Implications for Therapeutic Strategies.

Wang J, Shao F, Yu Q, Ye L, Wusiman D, Wu R Research (Wash D C). 2025; 8:0612.

PMID: 40046513 PMC: 11880593. DOI: 10.34133/research.0612.

Identification of diagnostic markers related to inflammatory response and cellular senescence in endometriosis using machine learning and in vitro experiment.

Yang P, Miao Y, Wang T, Sun J Inflamm Res. 2024; 73(7):1107-1122.

PMID: 38704432 DOI: 10.1007/s00011-024-01886-5.

ncRNAs-mediated TIMELESS overexpression in lung adenocarcinoma correlates with reduced tumor immune cell infiltration and poor prognosis.

Gao X, Tang M, Tian S, Li J, Wei S, Hua S PLoS One. 2024; 19(1):e0296829.

PMID: 38261568 PMC: 10805305. DOI: 10.1371/journal.pone.0296829.

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

Yang Y, Tang X, Lin Z, Zheng T, Zhang S, Liu T Eur J Med Res. 2023; 28(1):563.

PMID: 38053143 PMC: 10696727. DOI: 10.1186/s40001-023-01519-3.

TIMELESS upregulates PD-L1 expression and exerts an immunosuppressive role in breast cancer.

Dong X, Dai H, Lin Y, Sheng X, Li Y, Wang Y J Transl Med. 2023; 21(1):400.

PMID: 37340461 PMC: 10280842. DOI: 10.1186/s12967-023-04257-6.

References

McFarlane R, Mian S, Dalgaard J . The many facets of the Tim-Tipin protein families' roles in chromosome biology. Cell Cycle. 2010; 9(4):700-5. DOI: 10.4161/cc.9.4.10676. View

Gibson E, Williams 3rd W, Kriegsfeld L . Aging in the circadian system: considerations for health, disease prevention and longevity. Exp Gerontol. 2008; 44(1-2):51-6. PMC: 2636858. DOI: 10.1016/j.exger.2008.05.007. View

Yu E, Weaver D . Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes. Aging (Albany NY). 2011; 3(5):479-93. PMC: 3156599. DOI: 10.18632/aging.100323. View

Bondy S, Campbell A . Mechanisms Underlying Tumor Suppressive Properties of Melatonin. Int J Mol Sci. 2018; 19(8). PMC: 6121612. DOI: 10.3390/ijms19082205. View

Rivera L, Bergers G . Location, location, location: macrophage positioning within tumors determines pro- or antitumor activity. Cancer Cell. 2013; 24(6):687-9. PMC: 4243836. DOI: 10.1016/j.ccr.2013.11.014. View

Fu A, Leaderer D, Zheng T, Hoffman A, Stevens R, Zhu Y . Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk. Mol Carcinog. 2011; 51(12):923-9. DOI: 10.1002/mc.20862. View

Condeelis J, Pollard J . Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell. 2006; 124(2):263-6. DOI: 10.1016/j.cell.2006.01.007. View

James S, Honn K, Gaddameedhi S, Van Dongen H . Shift Work: Disrupted Circadian Rhythms and Sleep-Implications for Health and Well-Being. Curr Sleep Med Rep. 2017; 3(2):104-112. PMC: 5647832. DOI: 10.1007/s40675-017-0071-6. View

Warde-Farley D, Donaldson S, Comes O, Zuberi K, Badrawi R, Chao P . The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010; 38(Web Server issue):W214-20. PMC: 2896186. DOI: 10.1093/nar/gkq537. View

10.

Wang F, Chen Q . The analysis of deregulated expression of the genes in gliomas. J Cancer Res Ther. 2018; 14(Supplement):S708-S712. DOI: 10.4103/0973-1482.187382. View

11.

Haus E, Smolensky M . Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation. Sleep Med Rev. 2012; 17(4):273-84. DOI: 10.1016/j.smrv.2012.08.003. View

12.

Qian B, Pollard J . Macrophage diversity enhances tumor progression and metastasis. Cell. 2010; 141(1):39-51. PMC: 4994190. DOI: 10.1016/j.cell.2010.03.014. View

13.

Li J, Yang X, Wang Y, Feng M, Liu X, Zhang Y . Monoamine oxidase A suppresses hepatocellular carcinoma metastasis by inhibiting the adrenergic system and its transactivation of EGFR signaling. J Hepatol. 2014; 60(6):1225-34. DOI: 10.1016/j.jhep.2014.02.025. View

14.

Lozano-Lorca M, Olmedo-Requena R, Vega-Galindo M, Vazquez-Alonso F, Jimenez-Pacheco A, Salcedo-Bellido I . Night Shift Work, Chronotype, Sleep Duration, and Prostate Cancer Risk: CAPLIFE Study. Int J Environ Res Public Health. 2020; 17(17). PMC: 7503878. DOI: 10.3390/ijerph17176300. View

15.

Stone E, Fulton B, Ayres J, Pham L, Ziauddin J, Shirasu-Hiza M . The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila. PLoS Pathog. 2012; 8(1):e1002445. PMC: 3257305. DOI: 10.1371/journal.ppat.1002445. View

16.

Wang F, Yeung K, Chan W, Kwok C, Leung S, Wu C . A meta-analysis on dose-response relationship between night shift work and the risk of breast cancer. Ann Oncol. 2013; 24(11):2724-32. PMC: 7364178. DOI: 10.1093/annonc/mdt283. View

17.

Relles D, Sendecki J, Chipitsyna G, Hyslop T, Yeo C, Arafat H . Circadian gene expression and clinicopathologic correlates in pancreatic cancer. J Gastrointest Surg. 2012; 17(3):443-50. DOI: 10.1007/s11605-012-2112-2. View

18.

. Carcinogenicity of night shift work. Lancet Oncol. 2019; 20(8):1058-1059. DOI: 10.1016/S1470-2045(19)30455-3. View

19.

Hanahan D, Coussens L . Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012; 21(3):309-22. DOI: 10.1016/j.ccr.2012.02.022. View

20.

Torre L, Trabert B, DeSantis C, Miller K, Samimi G, Runowicz C . Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018; 68(4):284-296. PMC: 6621554. DOI: 10.3322/caac.21456. View