Abstract
Purpose
The prognosis of advanced gastric cancer (GC) remains poor. It is urgent and necessary to find suitable prognostic markers. miR-619-5p is highly expressed in GC. However, the value of miR-619-5p and its target genes as prognostic biomarkers of GC is unclear.
Methods
RT-PCR was performed to verify the expression of miR-619-5p in GC cell lines and their exosomes. Western blotting and transmission electron microscope were used to identify exosomes. The target genes of miR-619-5p were predicted by RNA22 and TargetScan. The differentially expressed genes (DEGs) and prognosis-related genes (PRGs) were obtained using The Cancer Genome Atlas (TCGA) database. The DAVID database was used to analyse pathway enrichment and functional annotation of common target genes. The STRING database and Cytoscape software were used to screen key genes and visualize their functional modules. The survival analysis was conducted using TCGA and Kaplan–Meier Plotter (KMP) databases. Finally, a prognostic model was constructed on the foundation of the key genes to assess the reliability of the screening process.
Results
The expression of miR-619-5p in GC cells and their exosomes was proved to be significantly higher than that in normal cell lines. There are 129 common target genes involved in 3 pathways and 28 functional annotations. Finally, nine key target genes of GC (BRCA1, RAD51, KIF11, ERCC6L, BRIP1, TIMELESS, CDC25A, CLSPN and NCAPG2) were identified, and a prognostic model was successfully constructed with a good predictive ability.
Conclusions
The model of 9-gene signature could effectively predict the prognosis of GC, and have great potential to be novel prognostic factors and therapeutic targets for patients with GC.
Similar content being viewed by others
Data availability
All data and results of this study are available from the corresponding author upon reasonable request.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49.
Xu Y, Huang C. Revisiting tumor marker CA72–4 in gastric cancer: as a biomarker, predictor, and therapeutic target. Biochim Biophys Acta. 2021;1876: 188634.
Feng RM, Zong YN, Cao SM, Xu RH. Current cancer situation in China: good or bad news from the 2018 Global Cancer Statistics? Cancer Commun (Lond). 2019;39(1):22.
Gong W, Zeng J, Ji J, Jia Y, Jia S, Sanders AJ, et al. EPLIN expression in gastric cancer and impact on prognosis and chemoresistance. Biomolecules. 2021;11(4):547.
Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet (London, England). 2020;396(10251):635–48.
Accordino G, Lettieri S, Bortolotto C, Benvenuti S, Gallotti A, Gattoni E, et al. From interconnection between genes and microenvironment to novel immunotherapeutic approaches in upper gastro-intestinal cancers-a multidisciplinary perspective. Cancers. 2020;12(8):2105.
Inoue J, Inazawa J. Cancer-associated miRNAs and their therapeutic potential. J Hum Genet. 2021;66(9):937–45.
Mishra S, Yadav T, Rani V. Exploring miRNA based approaches in cancer diagnostics and therapeutics. Crit Rev Oncol Hematol. 2016;98:12–23.
Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16(3):203–22.
Lee YS, Dutta A. MicroRNAs in cancer. Annu Rev Pathol. 2009;4:199–227.
Chen S, Gao C, Yu T, Qu Y, Xiao GG, Huang Z. Bioinformatics analysis of a prognostic miRNA signature and potential key genes in pancreatic cancer. Front Oncol. 2021;11: 641289.
Cai Y, Yu X, Hu S, Yu J. A brief review on the mechanisms of miRNA regulation. Genom Proteom Bioinform. 2009;7(4):147–54.
Chen L, Heikkinen L, Wang C, Yang Y, Sun H, Wong G. Trends in the development of miRNA bioinformatics tools. Brief Bioinform. 2019;20(5):1836–52.
Ren ZJ, Zhao Y, Wang G, Miao LL, Zhang ZC, Ma L, et al. Identification of differentially expressed miRNAs derived from serum exosomes associated with gastric cancer by microarray analysis. Clin Chim Acta. 2022;531:25–35.
Necula L, Matei L, Dragu D, Neagu AI, Mambet C, Nedeianu S, et al. Recent advances in gastric cancer early diagnosis. World J Gastroenterol. 2019;25(17):2029–44.
Yang G, Zhang Y, Yang J. A five-microRNA signature as prognostic biomarker in colorectal cancer by bioinformatics analysis. Front Oncol. 2019;9:1207.
Mu M, Niu W, Zhang X, Hu S, Niu C. LncRNA BCYRN1 inhibits glioma tumorigenesis by competitively binding with miR-619-5p to regulate CUEDC2 expression and the PTEN/AKT/p21 pathway. Oncogene. 2020;39(45):6879–92.
Kim DH, Park S, Kim H, Choi YJ, Kim SY, Sung KJ, et al. Tumor-derived exosomal miR-619–5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4. Cancer Lett. 2020;475:2–13.
Zhou C, Yi C, Yi Y, Qin W, Yan Y, Dong X, et al. LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/beta-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes. Mol Cancer. 2020;19(1):118.
Song A, Wu Y, Chu W, Yang X, Zhu Z, Yan E, et al. Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma. Int J Biol Sci. 2021;17(2):430–47.
Zheng Y, Song A, Zhou Y, Zhong Y, Zhang W, Wang C, et al. Identification of extracellular vesicles-transported miRNAs in Erlotinib-resistant head and neck squamous cell carcinoma. J Cell Commun Signal. 2020;14(4):389–402.
Okuda Y, Shimura T, Iwasaki H, Fukusada S, Nishigaki R, Kitagawa M, et al. Urinary microRNA biomarkers for detecting the presence of esophageal cancer. Sci Rep. 2021;11(1):8508.
Knyazev EN, Fomicheva KA, Mikhailenko DS, Nyushko KM, Samatov TR, Alekseev BY, et al. Plasma levels of hsa-miR-619-5p and hsa-miR-1184 differ in prostatic benign hyperplasia and cancer. Bull Exp Biol Med. 2016;161(1):108–11.
Shkurnikov MY, Makarova YA, Knyazev EN, Fomicheva KA, Galatenko AV, Nyushko KM, et al. Plasma level of hsa-miR-619-5p microRNA is associated with prostatic cancer dissemination beyond the capsule. Bull Exp Biol Med. 2017;163(4):475–7.
Qiu G, Zhang XB, Zhang SQ, Liu PL, Wu W, Zhang JY, et al. Dysregulation of MALAT1 and miR-619-5p as a prognostic indicator in advanced colorectal carcinoma. Oncol Lett. 2016;12(6):5036–42.
Hoppe MM, Sundar R, Tan DSP, Jeyasekharan AD. Biomarkers for homologous recombination deficiency in cancer. J Natl Cancer Inst. 2018;110(7):704–13.
Bonilla B, Hengel SR, Grundy MK, Bernstein KA. RAD51 gene family structure and function. Annu Rev Genet. 2020;54:25–46.
Xie C, Li N, Wang H, He C, Hu Y, Peng C, et al. Inhibition of autophagy aggravates DNA damage response and gastric tumorigenesis via Rad51 ubiquitination in response to H. pylori infection. Gut Microbes. 2020;11(6):1567–89.
Padua JDB, Mariano CFA, Fabro AT, Tirapelli D, Sankarankutty AK, Dos Santos JS, et al. Prognostic value of the immunohistochemical expression of RAD51 and BRCA2 in gastric adenocarcinoma. J Histochem Cytochem. 2022;70(3):199–210.
Lee A, Moon BI, Kim TH. BRCA1/BRCA2 pathogenic variant breast cancer: treatment and prevention strategies. Ann Lab Med. 2020;40(2):114–21.
Wang GH, Zhao CM, Huang Y, Wang W, Zhang S, Wang X. BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers. Hum Pathol. 2018;71:135–44.
Voutsadakis IA. Landscape of BRIP1 molecular lesions in gastrointestinal cancers from published genomic studies. World J Gastroenterol. 2020;26(11):1197–207.
Moyer CL, Ivanovich J, Gillespie JL, Doberstein R, Radke MR, Richardson ME, et al. Rare BRIP1 missense alleles confer risk for ovarian and breast cancer. Cancer Res. 2020;80(4):857–67.
Ji K, Ao S, He L, Zhang L, Feng L, Lyu G. Characteristics of cancer susceptibility genes mutations in 282 patients with gastric adenocarcinoma. Chin J Cancer Res. 2020;32(4):508–15.
Rath O, Kozielski F. Kinesins and cancer. Nat Rev Cancer. 2012;12(8):527–39.
Sun RF, He N, Zhang GY, Yu ZY, Li LS, Ma ZJ, et al. Combined inhibition of KIF11 and KIF15 as an effective therapeutic strategy for gastric cancer. Curr Cancer Drug Targets. 2023;23(4):293-306.
Ricci A, Gallorini M, Del Bufalo D, Cataldi A, D'Agostino I, Carradori S, et al. Negative Modulation of the Angiogenic Cascade Induced by Allosteric Kinesin Eg5 Inhibitors in a Gastric Adenocarcinoma In Vitro Model. Molecules. 2022;27(3): 957.
Chen H, Wang H, Yu X, Zhou S, Zhang Y, Wang Z, et al. ERCC6L promotes the progression of hepatocellular carcinoma through activating PI3K/AKT and NF-kappaB signaling pathway. BMC Cancer. 2020;20(1):853.
Zhang G, Yu Z, Fu S, Lv C, Dong Q, Fu C, et al. ERCC6L that is up-regulated in high grade of renal cell carcinoma enhances cell viability in vitro and promotes tumor growth in vivo potentially through modulating MAPK signalling pathway. Cancer Gene Ther. 2019;26(9–10):323–33.
Yu B, Liang H, Ye Q, Wang Y. Upregulation of ERCC6L is associated with tumor progression and unfavorable prognosis in hepatocellular carcinoma. J Gastrointest Oncol. 2020;11(5):1009–23.
Pu SY, Yu Q, Wu H, Jiang JJ, Chen XQ, He YH, et al. ERCC6L, a DNA helicase, is involved in cell proliferation and associated with survival and progress in breast and kidney cancers. Oncotarget. 2017;8(26):42116–24.
Chen D, Liu Q, Cao G. ERCC6L promotes cell growth and metastasis in gastric cancer through activating NF-kappaB signaling. Aging (Albany NY). 2021;13(16):20218–28.
Lo N, Rageul J, Kim H. Roles of SDE2 and TIMELESS at active and stalled DNA replication forks. Mol Cell Oncol. 2021;8(1):1855053.
Bianco JN, Bergoglio V, Lin YL, Pillaire MJ, Schmitz AL, Gilhodes J, et al. Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner. Nat Commun. 2019;10(1):910.
Yoshida K, Sato M, Hase T, Elshazley M, Yamashita R, Usami N, et al. TIMELESS is overexpressed in lung cancer and its expression correlates with poor patient survival. Cancer Sci. 2013;104(2):171–7.
Wang C, Zeng J, Li LJ, Xue M, He SL. Cdc25A inhibits autophagy-mediated ferroptosis by upregulating ErbB2 through PKM2 dephosphorylation in cervical cancer cells. Cell Death Dis. 2021;12(11):1055.
Guo SL, Ye H, Teng Y, Wang YL, Yang G, Li XB, et al. Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency. Nat Commun. 2013;4:2544.
Smits VAJ, Cabrera E, Freire R, Gillespie DA. Claspin—checkpoint adaptor and DNA replication factor. FEBS J. 2019;286(3):441–55.
Kobayashi G, Sentani K, Hattori T, Yamamoto Y, Imai T, Sakamoto N, et al. Clinicopathological significance of claspin overexpression and its association with spheroid formation in gastric cancer. Hum Pathol. 2019;84:8–17.
Wu J, Li L, Jiang G, Zhan H, Zhu X, Yang W. NCAPG2 facilitates glioblastoma cells’ malignancy and xenograft tumor growth via HBO1 activation by phosphorylation. Cell Tissue Res. 2021;383(2):693–706.
Acknowledgements
We thank all members in the Key Laboratory of Digestive System Tumours of Gansu Province.
Funding
This research was supported by Major Science and Technology Special Project of Gansu Province (20ZD7FA003), the Department of Science and Technology of Gansu Province (21JR1RA122), the Fundamental Research Funds for the central Universities (lzujbky-2021-ct18, lzujbky-2022-sp08), the Science Foundation of Gansu Province (20JR10RA732) and the Medical Research Improvement Project of Lanzhou University (lzuyxcx-2022-154).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflict of interest related to this publication.
Ethics approval
The manuscript does not contain clinical studies or patient data.
Consent for publication
All authors have read and agreed to all the contents for publication.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Wang, G., Ren, Z., Zhao, Y. et al. A nine-gene signature as prognostic biomarker in gastric cancer by bioinformatics analysis. Clin Transl Oncol 25, 3296–3306 (2023). https://doi.org/10.1007/s12094-023-03180-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-023-03180-y