Advertisement

E2F7, EREG, miR-451a and miR-106b-5p are associated with the cervical cancer development

  • Shan Zong
  • Xiaoxia Liu
  • Na Zhou
  • Ying YueEmail author
Gynecologic Oncology
  • 58 Downloads

Abstract

Purpose

We aimed to seek the crucial genes or microRNAs (miRNA) correlated with the cervical cancer development.

Methods

The miRNA profiling GSE30656 and gene expression profiling GSE63514 were obtained from Gene Expression Omnibus database. Differentially expressed microRNAs (DEMiRs) and differentially expressed genes (DEGs) were screened. Then target genes of DEMiRs were obtained and matched with DEGs to obtain interaction pairs between DEMiRs and DEGs. Gene Ontology-biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for DEGs and DEMiRs in the DEMiRs–DEGs pairs. The DEMiRs–DEGs regulatory network, protein–protein interaction network and transcription factor (TF)–target regulatory network were constructed. Ultimately, long non-coding RNAs (lncRNAs) associated with DEMiRs were obtained, and then lncRNA–miRNA–target ceRNA network was established.

Results

Total 18 DEMiRs and 620 DEGs were identified. DEMiRs were enriched in 35 KEGG pathways, such as PI3K–Akt signaling pathway (involving miR-451a). DEGs were enriched in various functions, such as DNA replication (involving E2F7) and angiogenesis (involving EREG). There were 120 nodes and 216 interaction pairs in the DEMIR–DEG regulatory network, and miR-106b-5p has the greatest degree. EREG and E2F7 were regulated by miR-451a and miR-148a-3p, respectively. Besides, E2F7 was identified in the TF–target regulatory network, regulating CDC6. There were 15 lncRNAs, 11 miRNAs and 90 DEGs in the ceRNA network. Specially, miR-148a-3p was interacted with lncRNA HOTAIR in the ceRNA network.

Conclusion

E2F7, EREG, miR-451a and miR-106b-5p were likely to be related to the cervical cancer development.

Keywords

Cervical cancer Differentially expressed miRNAs Differentially expressed genes Regulatory network Angiogenesis 

Abbreviations

miRNA

MicroRNAs

DEGs

Differentially expressed genes

DEMiRs

Differentially expressed microRNAs

KEGG

Kyoto encyclopedia of genes and genomes

TFs

Transcription factors

lncRNAs

Long non-coding RNAs

GEO

Gene expression omnibus

BH

Benjamini and Hochberg

FC

Fold change

GO-BP

Gene ontology biological process

ORA

Enrichment analysis

NES

Normalized enrichment score

PCA

Principal component analysis

MAPK1

Mitogen-activated protein kinase 1

Notes

Author contributions

SZ and YY contributed to the conceptualization. XL and NZ acquired and interpreted the data. SZ explained some important intellectual content and drafted the manuscript. YY revised the manuscript and is responsible for the further intellectual explanation and correspondence.

Compliance with ethical standards

Ethical statement

Not applicable.

Conflict of interest

The authors report no conflict of interest.

References

  1. 1.
    Petry K (2014) HPV and cervical cancer. Scand J Clin Lab Invest Suppl 244:59–62 (discussion 62) CrossRefGoogle Scholar
  2. 2.
    Arbyn M, Castellsagué X, de Sanjosé S, Bruni L, Saraiya M, Bray F, Ferlay J (2011) Worldwide burden of cervical cancer in 2008. Ann Oncol 22(12):2675–2686CrossRefGoogle Scholar
  3. 3.
    Kent A (2010) HPV vaccination and testing. Rev Obstet Gynecol 3(1):33–34PubMedPubMedCentralGoogle Scholar
  4. 4.
    Bosch FX, Lorincz A, Muñoz N, Meijer CJLM, Shah KV (2002) The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55(4):244–265CrossRefGoogle Scholar
  5. 5.
    Gadducci A, Barsotti C, Cosio S, Domenici L, Riccardo Genazzani A (2011) Smoking habit, immune suppression, oral contraceptive use, and hormone replacement therapy use and cervical carcinogenesis: a review of the literature. Gynecol Endocrinol 27(8):597–604CrossRefGoogle Scholar
  6. 6.
    Zur-Hausen H (2009) Papillomaviruses in the causation of human cancers—a brief historical account. Virology 384(2):260–265CrossRefGoogle Scholar
  7. 7.
    Wang F, Tan W, Liu W, Jin Y, Dong D, Zhao X, Liu Q (2018) Effects of miR-214 on cervical cancer cell proliferation, apoptosis and invasion via modulating PI3K/AKT/mTOR signal pathway. Eur Rev Med Pharmacol Sci 22(7):1891–1898PubMedGoogle Scholar
  8. 8.
    Gao C, Zhou C, Zhuang J, Liu L, Liu C, Li H, Liu G, Wei J, Sun C (2018) MicroRNA expression in cervical cancer: novel diagnostic and prognostic biomarkers. J Cell Biochem 119(8):7080–7090CrossRefGoogle Scholar
  9. 9.
    Shan D, Shang Y, Hu T (2018) MicroRNA-411 inhibits cervical cancer progression by directly targeting STAT3. Oncol Res.  https://doi.org/10.3727/096504018X15247361080118 CrossRefPubMedGoogle Scholar
  10. 10.
    Hu Q, Song J, Ding B, Cui Y, Liang J, Han S (2018) miR-146a promotes cervical cancer cell viability via targeting IRAK1 and TRAF6. Oncol Rep 39(6):3015–3024PubMedGoogle Scholar
  11. 11.
    Zhang Y, Cheng X, Liang H, Jin Z (2018) Long non-coding RNA HOTAIR and STAT3 synergistically regulate the cervical cancer cell migration and invasion. Chem Biol Interact 286:106–110CrossRefGoogle Scholar
  12. 12.
    Wilting S, Snijders P, Verlaat W, Jaspers A, van de Wiel M, van Wieringen W, Meijer G, Kenter G, Yi Y, le Sage C, Agami R, Meijer C, Steenbergen R (2013) Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis. Oncogene 32(1):106–116CrossRefGoogle Scholar
  13. 13.
    den Boon J, Pyeon D, Wang S, Horswill M, Schiffman M, Sherman M, Zuna R, Wang Z, Hewitt S, Pearson R, Schott M, Chung L, He Q, Lambert P, Walker J, Newton M, Wentzensen N, Ahlquist P (2015) Molecular transitions from papillomavirus infection to cervical precancer and cancer: role of stromal estrogen receptor signaling. Proc Natl Acad Sci USA 112(25):E3255–E3264CrossRefGoogle Scholar
  14. 14.
    Carvalho BS, Irizarry RA (2010) A framework for oligonucleotide microarray preprocessing. Bioinformatics 26(19):2363–2367.  https://doi.org/10.1093/bioinformatics/btq431 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Smyth GK (2005) limma: Linear models for microarray data. In: Gentleman R, Carey VJ, Huber W, Irizarry RA, Dudoit S (eds) Bioinformatics and computational biology solutions using R and bioconductor. Statistics for biology and health. Springer, New York, NY.  https://doi.org/10.1007/0-387-29362-0_23 CrossRefGoogle Scholar
  16. 16.
    Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate—a practical and powerful approach to multiple testing. J R Stat Soc 57(1):289–300Google Scholar
  17. 17.
    Dweep H, Gretz N (2015) miRWalk2.0: a comprehensive atlas of microRNA–target interactions. Nat Methods 12(8):697.  https://doi.org/10.1038/nmeth.3485. http://www.nature.com/nmeth/journal/v12/n8/abs/nmeth.3485.html#supplementary-information
  18. 18.
    Yu G, Wang LG, Han Y, He QY (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. Omics J Integr Biol 16(5):284–287CrossRefGoogle Scholar
  19. 19.
    Kanehisa M, Goto S (2000) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 27(1):29–34Google Scholar
  20. 20.
    Sherlock G (2009) Gene Ontology: tool for the unification of biology. Can Inst Food Sci Technol J 22(4):415Google Scholar
  21. 21.
    Zhang B, Kirov S, Snoddy J (2005) WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res 33(web server issue):741–748CrossRefGoogle Scholar
  22. 22.
    Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13(11):2498–2504.  https://doi.org/10.1101/gr.1239303 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, Doerks T, Stark M, Muller J, Bork P (2011) The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 39(database issue):561–568CrossRefGoogle Scholar
  24. 24.
    Janky RS, Verfaillie A, Imrichová H, Sande BVD, Standaert L, Christiaens V, Hulselmans G, Herten K, Sanchez MN, Potier D (2014) iRegulon: from a gene list to a gene regulatory network using large motif and track collections. PLoS Comput Biol 10(7):e1003731CrossRefGoogle Scholar
  25. 25.
    Li JH, Liu S, Zhou H, Qu LH, Yang JH (2014) starBase v2.0: decoding miRNA–ceRNA, miRNA–ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res 42(database issue):92CrossRefGoogle Scholar
  26. 26.
    Folkman J (1992) Angiogenesis. J Biol Chem 267(16):1–18Google Scholar
  27. 27.
    Landt S, Mordelt K, Schwidde I, Barinoff J, Korlach S, Stãblen F, Lichtenegger W, Sehouli J, Kãmmel S (2011) Prognostic significance of the angiogenic factors angiogenin, endoglin and endostatin in cervical cancer. Anticancer Res 31(8):2651–2655PubMedGoogle Scholar
  28. 28.
    Liu H, Xiao J, Yang Y, Liu Y, Ma R, Li Y, Deng F, Zhang Y (2011) COX-2 expression is correlated with VEGF-C, lymphangiogenesis and lymph node metastasis in human cervical cancer. Microvasc Res 82(2):131–140CrossRefGoogle Scholar
  29. 29.
    Zhang W, Wu Q, Wang C, Yang L, Liu P, Ma C (2018) AKIP1 promotes angiogenesis and tumor growth by upregulating CXC-chemokines in cervical cancer cells. Mol Cell Biochem 1:1–10Google Scholar
  30. 30.
    Zeng T, Peng L, Chao C, Fu B, Wang G, Wang Y, Zhu X (2014) miR-451 inhibits invasion and proliferation of bladder cancer by regulating EMT. Int J Clin Exp Pathol 7(11):7653–7662PubMedPubMedCentralGoogle Scholar
  31. 31.
    Liu X, Zhang A, Xiang J, Lv Y, Zhang X (2016) miR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway. Oncol Rep 36(3):1385–1392CrossRefGoogle Scholar
  32. 32.
    Xu H, Mei Q, Shi L, Lu J, Zhao J, Fu Q (2014) Tumor-suppressing effects of miR451 in human osteosarcoma. Cell Biochem Biophys 69(1):163–168CrossRefGoogle Scholar
  33. 33.
    Qian S, Li M (2017) Chamaejasmine induces apoptosis in HeLa cells through the PI3K/Akt signaling pathway. Anticancer Drugs 28(1):40CrossRefGoogle Scholar
  34. 34.
    Jeyamohan S, Moorthy RK, Kannan MK, Arockiam AJV (2016) Parthenolide induces apoptosis and autophagy through the suppression of PI3K/Akt signaling pathway in cervical cancer. Biotech Lett 38(8):1251–1260CrossRefGoogle Scholar
  35. 35.
    Li A, Gu Y, Li X, Sun H, Zha H, Xie J, Zhao J, Huang M, Chen L, Peng Q (2018) S100A6 promotes the proliferation and migration of cervical cancer cells via the PI3K/Akt signaling pathway. Oncol Lett 15(4):5685–5693PubMedPubMedCentralGoogle Scholar
  36. 36.
    Zhang W, Xiong Z, Wei T, Li Q, Tan Y, Ling L, Feng X (2018) Nuclear factor 90 promotes angiogenesis by regulating HIF-1α/VEGF-A expression through the PI3K/Akt signaling pathway in human cervical cancer. Cell Death Dis 9(3):276CrossRefGoogle Scholar
  37. 37.
    Mazurek A, Luo W, Krasnitz A, Hicks J, Powers RS, Stillman B (2012) DDX5 regulates DNA replication and is required for cell proliferation in a subset of breast cancer cells. Cancer Discov 2(9):812CrossRefGoogle Scholar
  38. 38.
    Costa A, Hood IV, Berger JM (2013) Mechanisms for initiating cellular DNA replication. Annu Rev Biochem 82(82):25CrossRefGoogle Scholar
  39. 39.
    Liu D, Zhang XX, Xi BX, Wan DY, Li L, Zhou J, Wang W, Ma D, Wang H, Gao QL (2014) Sine oculis homeobox homolog 1 promotes DNA replication and cell proliferation in cervical cancer. Int J Oncol 45(3):1232CrossRefGoogle Scholar
  40. 40.
    Wang WX, Zhang WJ, Peng ZL, Yang KX (2009) Expression and clinical significance of CDC6 and hMSH2 in cervical carcinoma. J Sichuan Univ 40(5):857–860Google Scholar
  41. 41.
    Yang TS, Yang XH, Chen X, Wang XD, Hua J, Zhou DL, Zhou B, Song ZS (2014) MicroRNA-106b in cancer-associated fibroblasts from gastric cancer promotes cell migration and invasion by targeting PTEN. FEBS Lett 588(13):2162–2169CrossRefGoogle Scholar
  42. 42.
    Song E (2013) MiR-106b expression determines the proliferation paradox of TGF-|[beta]| in breast cancer cells. Oncogene 34(1):84–93PubMedGoogle Scholar
  43. 43.
    Prasad R, Katiyar SK (2014) Down-regulation of miRNA-106b inhibits growth of melanoma cells by promoting G1-phase cell cycle arrest and reactivation of p21/WAF1/Cip1 protein. Oncotarget 5(21):10636–10649CrossRefGoogle Scholar
  44. 44.
    Cheng Y, Guo Y, Zhang Y, You K, Li Z, Geng L (2016) MicroRNA-106b is involved in transforming growth factor β1-induced cell migration by targeting disabled homolog 2 in cervical carcinoma. J Exp Clin Cancer Res 35(1):1–11CrossRefGoogle Scholar
  45. 45.
    Piao J, You K, Guo Y, Zhang Y, Li Z, Geng L (2017) Substrate stiffness affects epithelial–mesenchymal transition of cervical cancer cells through miR-106b and its target protein DAB2. Int J Oncol 50(6):2033–2042CrossRefGoogle Scholar
  46. 46.
    Gao D, Zhang Y, Zhu M, Liu S, Wang X (2016) miRNA expression profiles of HPV-infected patients with cervical cancer in the Uyghur population in China. PLoS ONE 11(10):e0164701CrossRefGoogle Scholar
  47. 47.
    Liu M, Jia J, Wang X, Liu Y, Wang C (2018) Long non-coding RNA HOTAIR promotes cervical cancer progression through regulating BCL2 via targeting miR-143-3p. Cancer Biol Ther 19:1–9CrossRefGoogle Scholar
  48. 48.
    Li Q, Feng Y, Chao X, Shi S, Liang M, Qiao Y, Wang B, Wang P, Zhu Z (2018) HOTAIR contributes to cell proliferation and metastasis of cervical cancer via targeting miR-23b/MAPK1 axis. Biosci Rep 38(1):BSR20171563CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Gynecology OncologyThe First Hospital of Jilin UniversityChang ChunChina
  2. 2.Department of Gynecology and ObstetricThe First Hospital of Jilin UniversityChang ChunChina

Personalised recommendations