Abstract
Cervical cancer is a serious threat to women’s health. The aim of this study was to provide new insights into the mechanism of cervical cancer by constructing immune-related prognostic model and ceRNA network. The mRNA and circRNA datasets of cervical cancer were downloaded from NCBI GEO database. Wilcox.test was used to screen the differential immune cells between cervical cancer patients and normal participants. WGCNA was performed for identification immune related genes. A circRNA-lncRNA-mRNA network was constructed and the genes in the network were further screened for genes related to prognosis using survival package in R software. The prognostic risk model was further validated in the TCGA database. Finally, GSEA was performed to investigate the different enrichment pathways between high_risk and low_risk groups. Nine genes (BEX4, CCL14, CCL3, CMPK2, FMOD, GHR, HLF, IGFBP5, PAG1) were selected to construct the prognostic model. Patients in the low_risk group had a significantly better prognosis than those in the high_risk group. hsa_circ_0021727-hsa-miR-133b-PAG1 regulatory axis may participate in the regulatory of cervical cancer. The enrichment pathways to patients in the high-risk group and the low-risk group were different. The results were not validated by in vitro and in vivo experiments. We developed an immune-related prognostic model and lncRNA-miRNA-mRNA ceRNA network, which can predict prognosis and understand the mechanism of cervical cancer.
DATA AVAILABILITY
All data generated or analyzed during this study are included in this article and its supplementary material files. Further enquiries can be directed to the corresponding author.
REFERENCES
Hull, R., Mbele, M., Makhafola, T., et al., Cervical cancer in low and middle‑income countries, Oncol. Lett., 2020, vol. 20, no. 3, pp. 2058—2074.
Yuan, Y., Cai, X., Shen, F., et al., HPV post-infection microenvironment and cervical cancer, Cancer Lett., 2021, vol. 497, pp. 243—254.
Hashim, D., Engesæter, B., Skare, G.B., et al., Real-world data on cervical cancer risk stratification by cytology and HPV genotype to inform the management of HPV-positive women in routine cervical screening, Brit. J. Cancer, 2020, vol. 122, no. 11, pp. 1715—1723.
Wang, J., Wang, T., Yang, Y.Y., et al., Patient age, tumor appearance and tumor size are risk factors for early recurrence of cervical cancer, Mol. Clin. Oncol., 2015, vol. 3, no. 2, pp. 363—366.
Nahand, J.S., Vandchali, N.R., Darabi, H., et al., Exosomal microRNAs: novel players in cervical cancer, Epigenomics, 2020, vol. 12, no. 18, pp. 1651—1660.
Chen, R.X., Liu, H.L., Yang, L.L., et al., Circular RNA circRNA_0000285 promotes cervical cancer development by regulating FUS, Eur. Rev. Med. Pharmacol. Sci., 2019, vol. 23, no. 20, pp. 8771—8778.
Patop, I.L., Wüst, S., and Kadener, S., Past, present, and future of circRNAs, EMBO J., 2019, vol. 38, no. 16, p. e100836.
Wu, W. and Zou, J., Studies on the role of circRNAs in osteoarthritis, Biomed. Res. Int., 2021, vol. 2021, p. 8231414.
Kulcheski, F.R., Christoff, A.P., and Margis, R., Circular RNAs are miRNA sponges and can be used as a new class of biomarker, J. Biotechnol., 2016, vol. 238, pp. 42—51.
Xu, Y., Qiu, A., Peng, F., et al., Exosomal transfer of circular RNA FBXW7 ameliorates the chemoresistance to oxaliplatin in colorectal cancer by sponging miR-18b-5p, Neoplasma, 2021, vol. 68, no. 1, pp. 108—118.
Gao, Y.L., Zhang, M.Y., Xu, B., et al., Circular RNA expression profiles reveal that hsa_circ_0018289 is up-regulated in cervical cancer and promotes the tumorigenesis, Oncotarget, 2017, vol. 8, no. 49, pp. 86625—86633.
Liu, J., Wang, D., Long, Z., et al., CircRNA8924 promotes cervical cancer cell proliferation, migration and invasion by competitively binding to MiR-518d-5p /519-5p family and modulating the expression of CBX8, Cell Physiol. Biochem., 2018, vol. 48, no. 1, pp. 173—184.
Tian, J.D.C. and Liang, L., Involvement of circular RNA SMARCA5/microRNA-620 axis in the regulation of cervical cancer cell proliferation, invasion and migration, Eur. Rev. Med. Pharmacol. Sci., 2018, vol. 22, no. 24, pp. 8589—8598.
Fridman, W.H., Zitvogel, L., Sautès-Fridman, C., et al., The immune contexture in cancer prognosis and treatment, Nat. Rev. Clin. Oncol., 2017, vol. 14, no. 12, pp. 717—734.
Li, R., Liu, Y., Yin, R., et al., The dynamic alternation of local and systemic tumor immune microenvironment during concurrent chemoradiotherapy of cervical cancer: a prospective clinical trial, Int. J. Radiat. Oncol. Biol. Phys., 2021, vol. 110, no. 5.
Zappa, C. and Mousa, S.A., Non-small cell lung cancer: current treatment and future advances, Transl. Lung Cancer R., vol. 5, no. 3, pp. 288—300.
Barrett, T., Suzek, T.O., Troup, D.B., et al., NCBI GEO: mining millions of expression profiles—database and tools, Nucleic Acids Res., 2005, vol. 33, suppl. 1, pp. D562—D566.
Leek, J.T., Johnson, W.E., Parker, H.S., et al., The SVA package for removing batch effects and other unwanted variation in high-throughput experiments, Bioinformatics, 2012, vol. 28, no. 6, pp. 882—883.
Nikolayeva, O. and Robinson, M.D., edgeR for differential RNA-seq and ChIP-seq analysis: an application to stem cell biology, in Stem Cell Transcriptional Networks, Kidder, B., Ed., Methods in Molecular Biology, New York: Humana Press, 2014, vol. 1150, pp. 45—79. https://doi.org/10.1007/978-1-4939-0512-6_3
Robinson, M.D., McCarthy, D.J. and Smyth, G.K., edgeR: a bioconductor package for differential expression analysis of digital gene expression data, Bioinformatics, 2010, vol. 26, no. 1, pp. 139—140.
Gu, Z. and Huebschmann, D., simplifyEnrichment: an R/bioconductor package for clustering and visualizing functional enrichment results, genomics proteomics Bioinformatics, 2021, vol. 21, no. 1, pp. 190—202.
Szklarczyk, D., Franceschini, A., Wyder, S., et al., STRING v10: protein—protein interaction networks, integrated over the tree of life, Nucleic Acids Res., 2015, vol. 43, no. D1, pp. D447—D452.
Smyth, G.K., Ritchie, M., Thorne, N., et al., LIMMA: linear models for microarray data, in Bioinformatics and Computational Biology Solutions Using R and Bioconductor Statistics for Biology and Health, 2005.
Ashburner, M., Ball, C., Blake, J., et al., Gene Ontology: tool for the unification of biology, Nat. Genet., 2000, vol. 25, pp. 25—29. https://doi.org/10.1038/75556
Kanehisa, M. and Goto, S., KEGG: Kyoto encyclopedia of genes and genomes, Nucleic Acids Res., 2000, vol. 28, no. 1, pp. 27—30.
Yu, G., Wang, L.-G., Han, Y., et al., clusterProfiler: an R package for comparing biological themes among gene clusters, Omics, 2012, vol. 16, no. 5, pp. 284—287.
Therneau, T. and Lumley, T., R Survival Package, 2013.
Sohn, I., Kim, J., Jung, S.-H., et al., Gradient lasso for Cox proportional hazards model, Bioinformatics, 2009, vol. 25, no. 14, pp. 1775—1781.
Friedman, J., Hastie, T. and Tibshirani, R., Regularization paths for generalized linear models via coordinate descent, J. Stat. Software, 2010, vol. 33, no. 1, p. 1.
Van Meir, H., Nout, R., Welters, M., et al., Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients, Oncoimmunology, 2017, vol. 6, no. 2, p. e1267095.
Stone, S.C., Rossetti, R.A.M., Alvarez, K.L.F., et al., Lactate secreted by cervical cancer cells modulates macrophage phenotype, J. Leukoc. Biol., 2019, vol. 105, no. 5, pp. 1041—1054.
Liu, Y., Li, L., Li, Y., et al., Research progress on tumor-associated macrophages and inflammation in cervical cancer, Biomed. Res. Int., 2020, vol. 2020, p. 6842963. https://doi.org/10.1155/2020/6842963
Yang, L., Yang, Y., Meng, M., et al., Identification of prognosis-related genes in the cervical cancer immune microenvironment, Gene, 2021, vol. 766, p. 145119.
van Leeuwen, E.M., Sprent, J. and Surh, C.D., Generation and maintenance of memory CD4+ T cells, Curr. Opin. Immunol., 2009, vol. 21, no. 2, pp. 167—172.
Liu, W., Chen, B., Yao, J., et al., Identification of fish CMPK2 as an interferon stimulated gene against SVCV infection, Fish Shellfish Immun., 2019, vol. 92, pp. 125—132.
Lai, J.-H., Hung, L.-F., Huang, C.-Y., et al., Mitochondrial protein CMPK2 regulates IFN alpha-enhanced foam cell formation, potentially contributing to premature atherosclerosis in SLE, Arthritis Res. Ther., 2021, vol. 23, no. 1, pp. 1—12.
Korbecki, J., Grochans, S., Gutowska, I., et al., CC chemokines in a tumor: a review of pro-cancer and anti-cancer properties of receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 ligands, Int. J. Mol. Sci., 2020, vol. 21, no. 20.
Halle, M.K., Munk, A.C., Engesæter, B., et al., A gene signature identifying CIN3 regression and cervical cancer survival, Cancers, 2021, vol. 13, no. 22, p. 5737.
Ayala-Calvillo, E., Mojica-Vázquez, L.H., García-Carrancá, A., et al., Wnt/β‑catenin pathway activation and silencing of the APC gene in HPV‑positive human cervical cancer‑derived cells, Mol. Med. Rep., 2018, vol. 17, no. 1, pp. 200—208.
Ben-Sahra, I. and Manning, B.D., mTORC1 signaling and the metabolic control of cell growth, Curr. Opin. Cell Biol., 2017, vol. 45, pp. 72—82.
Bossler, F., Hoppe-Seyler, K. and Hoppe-Seyler, F., PI3K/AKT/mTOR signaling regulates the virus/host cell crosstalk in HPV-positive cervical cancer cells, Int. J. Mol. Sci., 2019, vol. 20, no. 9, p. 2188.
Dan, V.M., Muralikrishnan, B., Sanawar, R., et al., Streptomyces sp. metabolite(s) promotes Bax mediated intrinsic apoptosis and autophagy involving inhibition of mTOR pathway in cervical cancer cell lines, Sci. Rep., 2018, vol. 8, no. 1, pp. 1—13.
Shi, W., Gerster, K., Alajez, N.M., et al., MicroRNA-301 mediates proliferation and invasion in human breast cancer, Cancer Res., 2011, vol. 71, no. 8, pp. 2926—2937.
Qin, S., Gao, Y., Yang, Y., et al., Identifying molecular markers of cervical cancer based on competing endogenous RNA network analysis, Gynecol. Obstet. Invest., 2019, vol. 84, no. 4, pp. 350—359.
Agarwal, S., Ghosh, R., Chen, Z., et al., Transmembrane adaptor protein PAG1 is a novel tumor suppressor in neuroblastoma, Oncotarget, 2016, vol. 7, no. 17, p. 24018.
Luo, Q., Zhang, L., Fang, L., et al., Circular RNAs hsa_circ_0000479 in peripheral blood mononuclear cells as novel biomarkers for systemic lupus erythematosus, Autoimmunity, 2020, vol. 53, no. 3, pp. 167—176.
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Funding
This work was supported by the Huai’an Natural Science Research Program (HAB202206).
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Hongge Xu and Can Shi carried out the Conception and design of the research, Yingchun Gao participated in the Acquisition of data. Ting Zhang carried out the Analysis and interpretation of data. Jueying Zhao carried out in the design of the study and performed the statistical analysis. Can Shi and Hongge Xu conceived of the study, and participated in its design and coordination and helped to draft the manuscript and revision of manuscript for important intellectual content. All authors read and approved the final manuscript.
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Supplementary Information
Suppl. Fig. S1. Uniform manifold approximation and orojection for dimension reduction. (а) UMAP of samples before batch removal; (b) UMAP of samples after batch removal.
Suppl. Fig. S2. Flow chart.
Suppl. Fig. S3. The infiltration level of immune cells in the samples.
Suppl. Fig. S4. Parameters of LASSO model. (а) LASSO coefficient profiles; (b) LASSO deviance profiles.
Suppl. Fig. S5. ceRNA network of genes related with prognosis. The green circle and the red circle represent down-regulated and up-regulated genes, respectively. The blue and purple diamonds indicate down-regulation and up-regulation of circRNA, respectively. The triangle represents miRNA. The gray line indicates that circRNA competes to bind miRNA. The green connection indicates that miRNA regulates gene.
Suppl. Table S1. The information of enrolled database.
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Xu, H., Zhao, J., Zhang, T. et al. Development Immune-Related Prognostic Model and LncRNA-miRNA-mRNA ceRNA Network for Cervical Cancer. Russ J Genet 60, 375–386 (2024). https://doi.org/10.1134/S1022795424030165
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DOI: https://doi.org/10.1134/S1022795424030165