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Associated analysis of PER1/TUBB2B with endometrial cancer development caused by circadian rhythm disorders

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Abstract

Endometrial cancer (EC) is one of the most common gynecologic malignancies, and the incidence rate of night shift among women workers is higher than that in the general population. Circadian rhythm disorder, mainly rhythm gene, is related to various tumor onset, including EC. This study described the sleep/night-shift features of EC patients, explored the mechanism of the circadian clock gene PER and investigated prognostic and functional values of Per1 caused by night shift. A total of 619 subjects were enrolled and divided into two groups according to night-shift duties (rhythm group and control group), analyzed for clinical risk factors and night shift features of endometrial carcinoma. Then samples were randomly selected for sequencing and western blot were performed, and the function of overexpressed PER1 in ishikawa cells was explored. We noticed that severer EC patients experienced night-shift more frequently and with longer durations. A total of 58,174 differentially expressed genes were discovered, mainly rhythm genes and related to up and downstream regulatory genes. Western blot showed that the rhythm group had elevated protein expression of BCAS4, TUBB2B and RSPO4, and decreased expression of PER1 and PER2 in night-shift. In TCGA-EC datasets, PER1 was decreased in the EC patients with a significantly positive correlation with PER2, and higher PER1 expression indicated longer survival, opposite to TUBB2B. The research of overexpressing PER1 gene in EC ishikawa cells found that PER1 can promote apoptosis, expression of TNF-a, IL-6 and PD-1/PD-L1, inhibit the tumor invasion and expression of TUBB2B gene. Together, EC severity was associated with night-shift and rhythm disorders. The rhythm relating factors PER1, TUBB2B and tumor immune factors may regulate the mechanisms of EC onset and progression.

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Data availability

Availability of data and supporting materials section: “Please contact author for data requests. Please contact the email: tongwang@sxmu.edu.cn.

Abbreviations

LncRNA:

Long intergenic non-protein coding RNA

DEGs:

Differentially expressed genes

EC:

Endometrial cancer

GO:

Gene Ontology

KEGG:

Kyoto Encyclopedia of Genes and Genomes

OS:

Overall survival

R:

Rhythm

C:

Control

BCAS4:

Breast carcinoma amplified sequence 4

TUBB2B:

Tubulin beta-2B chain

RSPO4:

Roof Plate-Specific Spondin-4

PER1:

Period circadian regulator 1

PER2:

Period circadian regulator 2

Cklξ/δ:

TPTEP2-CSNK1E readthrough

Cry:

Crystallin

LGR4:

Leucine-rich repeat-containing G protein-coupled receptor 4

RNF43:

Ring finger protein 43

References

  1. Sanjida S, et al. How many patients enter EC surgery with psychotropic medication prescriptions, and how many receive a new prescription perioperatively? Gynecol Oncol. 2018;152:339–45.

    Article  Google Scholar 

  2. Shih HC, et al. Disturbance of circadian gene expression in EC: detection by real-time quantitative RT-PCR. Oncol Rep. 2005;14(6):1533–8.

    PubMed  CAS  Google Scholar 

  3. Rumble ME, et al. Circadian actigraphic rest-activity rhythms following surgery for EC: a prospective, longitudinal study. Gynecol Oncol. 2015;137(3):448–55.

    Article  Google Scholar 

  4. Zieker D, et al. Circadian expression of clock- and tumor suppressor genes in human oral mucosa. Cell Physiol Biochem. 2010;26(2):155–66.

    Article  CAS  Google Scholar 

  5. Yang X, et al. Down regulation of circadian clock gene Period 2 accelerates breast cancer growth by altering its daily growth rhythm. Breast Cancer Res Treat. 2009;117(2):423–31.

    Article  Google Scholar 

  6. Cogliano VJ, et al. Preventable exposures associated with human cancers. J Natl Cancer Inst. 2011;103(24):1827–39.

    Article  Google Scholar 

  7. Albrektsen G, et al. Parity and time interval since childbirth influence survival in EC patients. Int J Gynecol Cancer. 2009;19(4):665–9.

    Article  Google Scholar 

  8. Bevier M, Sundquist J, Hemminki K. Does the time interval between first and last birth influence the risk of endometrial and ovarian cancer? Eur J Cancer. 2011;47(4):586–91.

    Article  Google Scholar 

  9. Bjarnason GA, Jordan R. Circadian variation of cell proliferation and cell cycle protein expression in man: clinical implications. Prog Cell Cycle Res. 2000;4:193–206.

    Article  CAS  Google Scholar 

  10. Matsuo T, et al. Control mechanism of the circadian clock for timing of cell division in vivo. Science. 2003;302(5643):255–9.

    Article  CAS  Google Scholar 

  11. Panda S, et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell. 2002;109(3):307–20.

    Article  CAS  Google Scholar 

  12. Barbason H, et al. Importance of cell kinetics rhythmicity for the control of cell proliferation and carcinogenesis in rat liver (review). In Vivo. 1995;9(6):539–48.

    PubMed  CAS  Google Scholar 

  13. Hansen J. Increased breast cancer risk among women who work predominantly at night. Epidemiology. 2001;12(1):74–7.

    Article  CAS  Google Scholar 

  14. Tuyan Ilhan T, et al. Sleep quality of EC survivors and the effect of treatments. Turk J Obstet Gynecol. 2017;14(4):243–8.

    PubMed  PubMed Central  Google Scholar 

  15. Armbruster SD, et al. EC survivors’ sleep patterns before and after a physical activity intervention: a retrospective cohort analysis. Gynecol Oncol. 2018;149(1):133–9.

    Article  Google Scholar 

  16. Muter J, et al. The clock protein period 2 synchronizes mitotic expansion and decidual transformation of human endometrial stromal cells. FASEB J. 2015;29(4):1603–14.

    Article  CAS  Google Scholar 

  17. Shih MC, et al. Promoter methylation in circadian genes of ECs detected by methylation-specific PCR. Mol Carcinog. 2006;45(10):732–40.

    Article  CAS  Google Scholar 

  18. Yeh KT, et al. Abnormal expression of period 1 (PER1) in endometrial carcinoma. J Pathol. 2005;206(1):111–20.

    Article  CAS  Google Scholar 

  19. Coussy F, et al. Clinical value of R-spondins in triple-negative and metaplastic breast cancers. Br J Cancer. 2017;116(12):1595–603.

    Article  CAS  Google Scholar 

  20. Liu H, et al. Expression of regulatory factor R-spondin family in Wnt signaling pathway in colorectal cancer and its clinical significance. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2017;42(5):501–6.

    PubMed  Google Scholar 

  21. Nami B, et al. Genetics and expression profile of the tubulin gene superfamily in breast cancer subtypes and its relation to taxane resistance. Cancers (Basel). 2018;10(8):274.

    Article  CAS  Google Scholar 

  22. Romaniello R, et al. A novel mutation in the beta-tubulin gene TUBB2B associated with complex malformation of cortical development and deficits in axonal guidance. Dev Med Child Neurol. 2012;54(8):765–9.

    Article  Google Scholar 

  23. Guerrini R, et al. Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations. Eur J Hum Genet. 2012;20(9):995–8.

    Article  CAS  Google Scholar 

  24. Ruan Y, et al. Effect of TNFRSF6B neutralization antibody on cell growth suppression and apoptosis induction in glioma cells. Neoplasma. 2015;62(4):574–81.

    Article  CAS  Google Scholar 

  25. Chen G, Rong M, Luo D. TNFRSF6B neutralization antibody inhibits proliferation and induces apoptosis in hepatocellular carcinoma cell. Pathol Res Pract. 2010;206(9):631–41.

    Article  CAS  Google Scholar 

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Acknowledgements

All authors read and approved the final manuscript.

Funding

This work was supported by grants from China Post-doctoral Science Foundation Project (No. 2017M621107).

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Authors and Affiliations

  1. First Hospital of Shanxi Medical University, No. 85 Jiefang South Road, Taiyuan, 030001, Shanxi, China

    Zhaoxia Wang, Zhiping Jiang & Sanyuan Zhang

  2. School of Public Health, Shanxi Medical University, No. 56 Xinjian South Road, Taiyuan, 030001, Shanxi, China

    Hui Wang, Simin He & Tong Wang

  3. School of Basic Medical Sciences, Shanxi Medical University, No. 29 Jiefang South Road, Taiyuan, 030001, Shanxi, China

    Zhaojun Wang

  4. Affiliated Cancer Hospital of Shanxi Medical University, No. 3, Workers’ New Village, Xinghualing District, Taiyuan, 030001, Shanxi, China

    Changping Yan

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  1. Zhaoxia Wang
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  2. Hui Wang
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  3. Zhaojun Wang
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  4. Simin He
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  5. Zhiping Jiang
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  7. Sanyuan Zhang
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  8. Tong Wang
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Contributions

WZX, JZP, YCP and ZSY carried out the information collection of clinical questionnaire. WH, HSM and WT participated in the design of the study and performed the statistical analysis. WZX and WZJ carried out basic Molecular Biology experiments. WZX conceived of the study, and participated in its design and coordination and helped to draft the manuscript.

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Correspondence to Sanyuan Zhang or Tong Wang.

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The authors declare no competing interests.

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This study was approved by the Ethics Committee of Shanxi Medical University.

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Wang, Z., Wang, H., Wang, Z. et al. Associated analysis of PER1/TUBB2B with endometrial cancer development caused by circadian rhythm disorders. Med Oncol 37, 90 (2020). https://doi.org/10.1007/s12032-020-01415-4

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  • DOI: https://doi.org/10.1007/s12032-020-01415-4

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