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CDC25B is associated with the risk of hepatocellular carcinoma, but not related to persistent infection of hepatitis B virus in a Chinese population

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Abstract

The cell division cycle 25 (CDC25) gene members, including CDC25A, CDC25B and CDC25C, are reported to be associated with several human cancers. Here, we aim to investigate the association of functional polymorphisms of CDC25 gene family with the risk of hepatocellular carcinoma (HCC) and persistent infection of Hepatitis B virus (HBV) in a Chinese HBV-related population. First, we used bioinformatics tools to systematically screen functional polymorphisms within CDC25 gene family. Second, we evaluated the effects of candidate polymorphisms by recruiting 790 HCC cases, 709 persistent HBV carriers (PHC), and 741 subjects with HBV natural clearance (SHNC). MassARRAY platform was used for genotyping. At last, we conducted functional prediction and assay to further explore the pathogenic mechanism of the identified polymorphism. Our results demonstrated that CDC25B rs2295348 played a protective role in HCC risk in a HBV-related Chinese population (adjusted odds ratio [OR] = 0.77, 95% confidence interval [CI] 0.65–0.93, P = 0.006). It showed a more significantly reduced HCC risk in the SHNC population (adjusted OR = 0.73, 95% CI 0.59–0.89, P = 0.002). However, we did not observe the association between CDC25B rs2295348 and the risk of persistent HBV infection. Further functional prediction and assay demonstrated that the mutant A allele of CDC25B rs2295348 might significantly decrease gene expression to modify the HCC risk. Our results suggest that CDC25B rs2295348 may confer a protective effect on HCC risk in a HBV-related Chinese population, but do not influence the susceptibility to persistent HBV infection.

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Abbreviations

CDC25:

Cell division cycle 25

HCC:

Hepatocellular carcinoma

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

PHC:

Persistent HBV carriers

SHNC:

Subjects with HBV natural clearance

OR:

Odds ratio

CI:

Confidence interval

GWASs:

Genome-wide association studies

SNPs:

Single nucleotide polymorphisms

MAF:

Minor allele frequency

HWE:

Hardy–Weinberg equilibrium

ANOVA:

Analysis of variance

GCR:

Genotyping call rate

DMEM:

Dulbecco's modified eagle medium

FDR:

False discovery rate

HUST:

Huazhong University of Science and Technology

SD:

Standard deviation

Vs:

Versus

eQTL:

Expression quantitative trait loci

References

  1. Siegel RL, Miller KD, Jemal A (2019) Cancer statistics. CA: A Cancer J Clin 69(1):7–34. https://doi.org/10.3322/caac.21551

    Article  Google Scholar 

  2. Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, Al-Raddadi R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele TA, Barac A, Bensenor I, Berhane A, Bhutta Z, Castillo-Rivas J, Chitheer A, Choi JY, Cowie B, Dandona L, Dandona R, Dey S, Dicker D, Phuc H, Ekwueme DU, Zaki MS, Fischer F, Furst T, Hancock J, Hay SI, Hotez P, Jee SH, Kasaeian A, Khader Y, Khang YH, Kumar A, Kutz M, Larson H, Lopez A, Lunevicius R, Malekzadeh R, McAlinden C, Meier T, Mendoza W, Mokdad A, Moradi-Lakeh M, Nagel G, Nguyen Q, Nguyen G, Ogbo F, Patton G, Pereira DM, Pourmalek F, Qorbani M, Radfar A, Roshandel G, Salomon JA, Sanabria J, Sartorius B, Satpathy M, Sawhney M, Sepanlou S, Shackelford K, Shore H, Sun J, Mengistu DT, Topor-Madry R, Tran B, Ukwaja KN, Vlassov V, Vollset SE, Vos T, Wakayo T, Weiderpass E, Werdecker A, Yonemoto N, Younis M, Yu C, Zaidi Z, Zhu L, Murray CJL, Naghavi M, Fitzmaurice C (2017) The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the Global Burden of Disease Study 2015. JAMA Oncol 3(12):1683–1691. https://doi.org/10.1001/jamaoncol.2017.3055

    Article  PubMed  PubMed Central  Google Scholar 

  3. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ (2015) He J (2016) Cancer statistics in China. CA: A Cancer J Clin 66(2):115–132. https://doi.org/10.3322/caac.21338

    Article  CAS  Google Scholar 

  4. Liu Z, Jiang Y, Yuan H, Fang Q, Cai N, Suo C, Jin L, Zhang T, Chen X (2019) The trends in incidence of primary liver cancer caused by specific etiologies: results from the Global Burden of Disease Study 2016 and implications for liver cancer prevention. J Hepatol 70(4):674–683. https://doi.org/10.1016/j.jhep.2018.12.001

    Article  PubMed  Google Scholar 

  5. Khemlina G, Ikeda S, Kurzrock R (2017) The biology of Hepatocellular carcinoma: implications for genomic and immune therapies. Mol Cancer 16(1):149. https://doi.org/10.1186/s12943-017-0712-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Eichler EE, Flint J, Gibson G, Kong A, Leal SM, Moore JH, Nadeau JH (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11(6):446–450. https://doi.org/10.1038/nrg2809

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A, Godzik A, Hunter T, Dixon J, Mustelin T (2004) Protein tyrosine phosphatases in the human genome. Cell 117(6):699–711. https://doi.org/10.1016/j.cell.2004.05.018

    Article  CAS  PubMed  Google Scholar 

  8. Boutros R, Lobjois V, Ducommun B (2007) CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer 7(7):495–507. https://doi.org/10.1038/nrc2169

    Article  CAS  PubMed  Google Scholar 

  9. Liu JC, Granieri L, Shrestha M, Wang DY, Vorobieva I, Rubie EA, Jones R, Ju Y, Pellecchia G, Jiang Z, Palmerini CA, Ben-David Y, Egan SE, Woodgett JR, Bader GD, Datti A, Zacksenhaus E (2018) Identification of CDC25 as a common therapeutic target for triple-negative breast cancer. Cell Rep 23(1):112–126. https://doi.org/10.1016/j.celrep.2018.03.039

    Article  CAS  PubMed  Google Scholar 

  10. Wu C, Lyu J, Yang EJ, Liu Y, Zhang B, Shim JS (2018) Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells. Nat Commun 9(1):3212. https://doi.org/10.1038/s41467-018-05694-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Al-Matouq J, Holmes TR, Hansen LA (2019) CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death. Mol Carcinog 58(9):1691–1700. https://doi.org/10.1002/mc.23075

    Article  CAS  PubMed  Google Scholar 

  12. Yan X, Chua MS, He J, So SK (2008) Small interfering RNA targeting CDC25B inhibits liver tumor growth in vitro and in vivo. Mol Cancer 7:19. https://doi.org/10.1186/1476-4598-7-19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yin L, Chang C, Xu C (2017) G2/M checkpoint plays a vital role at the early stage of HCC by analysis of key pathways and genes. Oncotarget 8(44):76305–76317. https://doi.org/10.18632/oncotarget.19351

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhu X, Wu L, Yao J, Jiang H, Wang Q, Yang Z, Wu F (2015) MicroRNA let-7c inhibits cell proliferation and induces cell cycle arrest by targeting CDC25A in human hepatocellular carcinoma. PLoS ONE 10(4):e0124266. https://doi.org/10.1371/journal.pone.0124266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhong R, Tian J, Fu M, Ma S, Liu L, Li J, Shen N, Ke J, Yang Y, Gong Y, Zhu Y, Wang Y, Gong J, Chang J, Lei P, Cheng X, Huang K, Shen G, Miao X (2019) LINC01149 variant modulates MICA expression that facilitates hepatitis B virus spontaneous recovery but increases hepatocellular carcinoma risk. Oncogene. https://doi.org/10.1038/s41388-019-1117-7

    Article  PubMed  PubMed Central  Google Scholar 

  16. Shen N, Li L, Xu W, Tian J, Yang Y, Zhu Y, Gong Y, Ke J, Gong J, Chang J, Zhong R, Miao X (2019) A missense variant in PTPN12 associated with the risk of colorectal cancer by modifying Ras/MEK/ERK signaling. Cancer Epidemiol 59:109–114. https://doi.org/10.1016/j.canep.2019.01.013

    Article  PubMed  Google Scholar 

  17. Garcia-Closas M, Lubin JH (1999) Power and sample size calculations in case-control studies of gene-environment interactions: comments on different approaches. Am J Epidemiol 149(8):689–692. https://doi.org/10.1093/oxfordjournals.aje.a009876

    Article  CAS  PubMed  Google Scholar 

  18. Lammer C, Wagerer S, Saffrich R, Mertens D, Ansorge W, Hoffmann I (1998) The cdc25B phosphatase is essential for the G2/M phase transition in human cells. J Cell Sci 111(Pt 16):2445–2453

    CAS  PubMed  Google Scholar 

  19. Zhong Y, Yang J, Xu WW, Wang Y, Zheng CC, Li B, He QY (2017) KCTD12 promotes tumorigenesis by facilitating CDC25B/CDK1/Aurora A-dependent G2/M transition. Oncogene 36(44):6177–6189. https://doi.org/10.1038/onc.2017.287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Villanueva A (2019) Hepatocellular carcinoma. N Engl J Med 380(15):1450–1462. https://doi.org/10.1056/NEJMra1713263

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by National Natural Science Foundation of China (81601839).

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Authors and Affiliations

  1. Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Peng Wang

  2. Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jing Peng & Na Shen

  3. Department of Epidemiology and Biostatistics, MOE Key Laboratory of Environment & Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Yajie Gong

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  1. Peng Wang
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  2. Jing Peng
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  3. Yajie Gong
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  4. Na Shen
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Contributions

PW finished the main part experiment and data analysis, and drafted this manuscript; JP and YG finished the sample collection, part of the data collection and analysis. NS designed the project and reviewed the manuscript. All authors have read and approved this manuscript.

Corresponding author

Correspondence to Na Shen.

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The authors declare that they have no conflicts of interest.

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This study was approved by the institutional ethics committee of Tongji Hospital, Tongji Medical College of HUST (Wuhan, China). All procedures were in accordance with the guidelines and principles of Helsinki Declaration.

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All participants provided written informed consents.

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Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

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Wang, P., Peng, J., Gong, Y. et al. CDC25B is associated with the risk of hepatocellular carcinoma, but not related to persistent infection of hepatitis B virus in a Chinese population. Mol Biol Rep 47, 3361–3368 (2020). https://doi.org/10.1007/s11033-020-05408-4

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  • DOI: https://doi.org/10.1007/s11033-020-05408-4

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