Bioinformatics analysis of the interactions among lncRNA, miRNA and mRNA expression, genetic mutations and epigenetic modifications in hepatocellular carcinoma

Lin,Chengjie; Yuan,Guandou; Hu,Zhigao; Zeng,Yonglian; Qiu,Xiaoqiang; Yu,Hongping; He,Songqing

doi:10.3892/mmr.2018.9728

Bioinformatics analysis of the interactions among lncRNA, miRNA and mRNA expression, genetic mutations and epigenetic modifications in hepatocellular carcinoma

Authors:
- Chengjie Lin
- Guandou Yuan
- Zhigao Hu
- Yonglian Zeng
- Xiaoqiang Qiu
- Hongping Yu
- Songqing He
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China, Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
Published online on: December 5, 2018 https://doi.org/10.3892/mmr.2018.9728
Pages: 1356-1364

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study aimed to investigate the regulatory networks involving long noncoding RNA (lncRNA), microRNA (miRNA), mRNA, genetic mutations and epigenetic modifications in hepatocellular carcinoma (HCC) by analyzing datasets from The Cancer Genome Atlas (TCGA) database. TCGA was mined, and miRNAs, lncRNAs and mRNAs that were differentially expressed in HCC were identified using R software. A gene regulatory network was constructed using Cytoscape software. Representative genes were selected for functional enrichment analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. The associations among various proteins and protein networks were identified using the online software Search Tool for the Retrieval of Interacting Genes/Proteins. The cBioPortal database was used to analyze the association between genetic mutations and epigenetic modification, and the development of HCC. A total of 35 mRNAs were predicted to be targeted by 77 lncRNAs and 16 miRNAs, establishing a lncRNA‑miRNA‑mRNA regulatory network for HCC. Multivariable Cox regression analysis suggested that long intergenic non‑protein coding RNA 200, miRNA‑137, PDZ binding kinase and DNA polymerase θ were independent prognostic factors. In a regulatory network centered on miRNA‑424, six mRNA target genes were associated with HCC survival rates. Protein‑protein interaction analysis suggested that cell division cycle 25A (CDC25A) interacted with centrosomal protein 55 (CEP55), claspin, E2F transcription factor 7 and cyclin E1 (CCNE1. Mutations in CEP55 affected overall survival and disease‑free survival in HCC, whereas, mutations in CDC25A affected overall survival, and mutations in E2F7 affected disease‑free survival. Decreased methylation levels of CEP55, CDC25A and CCNE1 were associated with vascular invasion. The survival rate of patients with hypermethylation of CCNE1 and CEP55 was significantly associated with the rate of methylation of these loci. The present study provides an integrated bioinformatics analysis of gene expression, genetic mutations and epigenetic modifications that may be associated with the development of HCC.

View Figures

View References

1	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
2	Tang Z: Treatment strategies for cancer. Chin J Clin Hepatol. 27:337–339. 2011.(In Chinese).
3	Bartel DP: MicroRNAs: Target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
4	Krol J, Loedige I and Filipowicz W: The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 11:597–610. 2010. View Article : Google Scholar : PubMed/NCBI
5	Mercer TR and Mattick JS: Structure and function of long noncoding RNAs in epigenetic regulation. Nat Struct Mol Biol. 20:300–307. 2013. View Article : Google Scholar : PubMed/NCBI
6	Quinn JJ and Chang HY: Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 17:47–62. 2016. View Article : Google Scholar : PubMed/NCBI
7	Wapinski O and Chang HY: Long noncoding RNAs and human disease. Trends Cell Biol. 21:354–361. 2011. View Article : Google Scholar : PubMed/NCBI
8	Rozalski R, Gackowski D, Siomek-Gorecka A, Banaszkiewicz Z and Olinski R: Urinary measurement of epigenetic DNA modifications: A non-invasive assessment of the whole-body epigenetic status in healthy subjects and colorectal cancer patients. ChemistryOpen. 5:550–553. 2016. View Article : Google Scholar : PubMed/NCBI
9	Shakeri H, Fakhrjou A, Nikanfar A and Mohaddes-Ardebili SM: Methylation analysis of BRCA1 and APC in breast cancer and it's relationship to clinicopathological features. Clin Lab. 62:2333–2337. 2016. View Article : Google Scholar : PubMed/NCBI
10	Peng D, Zhang H and Sun G: The relationship between P16 gene promoter methylation and gastric cancer: A meta-analysis based on Chinese patients. J Cancer Res Ther. 10 Suppl:S292–S295. 2014. View Article : Google Scholar
11	Stephen JK, Chen KM, Merritt J, Chitale D, Divine G and Worsham MJ: Methylation markers for early detection and differentiation of follicular thyroid cancer subtypes. Cancer Clin Oncol. 4:1–12. 2015.PubMed/NCBI
12	Furukawa R, Hachiya T, Ohmomo H, Shiwa Y, Ono K, Suzuki S, Satoh M, Hitomi J, Sobue K and Shimizu A: Intraindividual dynamics of transcriptome and genome-wide stability of DNA methylation. Sci Rep. 6:264242016. View Article : Google Scholar : PubMed/NCBI
13	Liu XN, Liu XH, Yu XX, et al: DNA methylation of tumor suppressor genes and hepatocellular carcinoma. China Cancer. 26:727–732. 2017.(In Chinese).
14	Wang F, Ying HQ, He BS, Pan YQ, Deng QW, Sun HL, Chen J, Liu X and Wang SK: Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway. Oncotarget. 6:7899–7917. 2015.PubMed/NCBI
15	Zhang Z, Weaver DL, Olsen D, deKay J, Peng Z, Ashikaga T and Evans MF: Long non-coding RNA chromogenic in situ hybridisation signal pattern correlation with breast tumour pathology. J Clin Pathol. 69:76–81. 2016. View Article : Google Scholar : PubMed/NCBI
16	He JH, Han ZP, Liu JM, Zhou JB, Zou MX, Lv YB, Li YG and Cao MR: Overexpression of long non-coding RNA MEG3 inhibits proliferation of hepatocellular carcinoma Huh7 cells via negative modulation of miRNA-664. J Cell Biochem. 118:3713–3721. 2017. View Article : Google Scholar : PubMed/NCBI
17	Huang BP, Lin CS, Wang CJ and Kao SH: Upregulation of heat shock protein 70 and the differential protein expression induced by tumor necrosis factor-alpha enhances migration and inhibits apoptosis of hepatocellular carcinoma cell HepG2. Int J Med Sci. 14:284–293. 2017. View Article : Google Scholar : PubMed/NCBI
18	Ye Y, Wei Y, Xu Y, Li Y, Wang R, Chen J, Zhou Y, Fu Z, Chen Y, Wang X, et al: Induced MiR-1249 expression by aberrant activation of Hedegehog signaling pathway in hepatocellular carcinoma. Exp Cell Res. 355:9–17. 2017. View Article : Google Scholar : PubMed/NCBI
19	Wang J, Cao L, Wu J and Wang Q: Long non-coding RNA SNHG1 regulates NOB1 expression by sponging miR-326 and promotes tumorigenesis in osteosarcoma. Int J Oncol. 52:77–88. 2018.PubMed/NCBI
20	Zeng S, Xie X, Xiao YF, Tang B, Hu CJ, Wang SM, Wu YY, Dong H, Li BS and Yang SM: Long noncoding RNA LINC00675 enhances phosphorylation of vimentin on Ser83 to suppress gastric cancer progression. Cancer Lett. 412:179–187. 2018. View Article : Google Scholar : PubMed/NCBI
21	He JH, Han ZP, Zou MX, Wang L, Lv YB, Zhou JB, Cao MR and Li YG: Analyzing the LncRNA, miRNA and mRNA regulatory network in prostate cancer with bioinformatics software. J Comput Biol. 25:146–157. 2018. View Article : Google Scholar : PubMed/NCBI
22	Jiang H, Ma R, Zou S, Wang Y, Li Z and Li W: Reconstruction and analysis of the lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveal functional lncRNAs in rheumatoid arthritis. Mol Biosyst. 13:1182–1192. 2017. View Article : Google Scholar : PubMed/NCBI
23	Li DY, Chen WJ, Luo L, Wang YK, Shang J, Zhang Y, Chen G and Li SK: Prospective lncRNA-miRNA-mRNA regulatory network of long non-coding RNA LINC00968 in non-small cell lung cancer A549 cells: A miRNA microarray and bioinformatics investigation. Int J Mol Med. 40:1895–1906. 2017.PubMed/NCBI
24	Zhang Y, Li Y, Wang Q, Zhang X, Wang D, Tang HC, Meng X and Ding X: Identification of an lncRNA-miRNA-mRNA interaction mechanism in breast cancer based on bioinformatic analysis. Mol Med Rep. 16:5113–5120. 2017. View Article : Google Scholar : PubMed/NCBI
25	Zhang J, Fan D, Jian Z, Chen GG and Lai PB: Cancer specific long noncoding RNAs show differential expression patterns and competing endogenous RNA potential in hepatocellular carcinoma. PLoS One. 10:e01410422015. View Article : Google Scholar : PubMed/NCBI
26	He B, Yin J, Gong S, Gu J, Xiao J, Shi W, Ding W and He Y: Bioinformatics analysis of key genes and pathways for hepatocellular carcinoma transformed from cirrhosis. Medicine (Baltimore). 96:e69382017. View Article : Google Scholar : PubMed/NCBI
27	Kuznetsov VA, Tang Z and Ivshina AV: Identification of common oncogenic and early developmental pathways in the ovarian carcinomas controlling by distinct prognostically significant microRNA subsets. BMC Genomics. 18 Suppl 6:S6922017. View Article : Google Scholar
28	Fu Z, Han X, Du J, Han X, Liu W, Shao S and Liu X: Euphorbia lunulata extract acts on multidrug resistant gastric cancer cells to inhibit cell proliferation, migration and invasion, arrest cell cycle progression, and induce apoptosis. J Ethnopharmacol. 212:8–17. 2018. View Article : Google Scholar : PubMed/NCBI
29	El-Daly SM, Abba ML and Gamal-Eldeen AM: The role of microRNAs in photodynamic therapy of cancer. Eur J Med Chem. 142:550–555. 2017. View Article : Google Scholar : PubMed/NCBI
30	Xu X, Yamamoto H, Sakon M, Yasui M, Ngan CY, Fukunaga H, Morita T, Ogawa M, Nagano H, Nakamori S, et al: Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas. Clin Cancer Res. 9:1764–1772. 2003.PubMed/NCBI
31	Yuan P, Li J, Zhou F, Huang Q, Zhang J, Guo X, Lyu Z, Zhang H and Xing J: NPAS2 promotes cell survival of hepatocellular carcinoma by transactivating CDC25A. Cell Death Dis. 8:e27042017. View Article : Google Scholar : PubMed/NCBI
32	Jiang W, Huang H, Ding L, Zhu P, Saiyin H, Ji G, Zuo J, Han D, Pan Y, Ding D, et al: Regulation of cell cycle of hepatocellular carcinoma by NF90 through modulation of cyclin E1 mRNA stability. Oncogene. 34:4460–4470. 2015. View Article : Google Scholar : PubMed/NCBI
33	Zhang X, Hu S, Zhang X, Wang L, Zhang X, Yan B, Zhao J, Yang A and Zhang R: MicroRNA-7 arrests cell cycle in G1 phase by directly targeting CCNE1 in human hepatocellular carcinoma cells. Biochem Biophys Res Commun. 443:1078–1084. 2014. View Article : Google Scholar : PubMed/NCBI
34	Bahrami A, Hesari A, Khazaei M, Hassanian SM, Ferns GA and Avan A: The therapeutic potential of targeting the BRAF mutation in patients with colorectal cancer. J Cell Physiol. 233:2162–2169. 2018. View Article : Google Scholar : PubMed/NCBI
35	Vietsch EE, Graham GT, McCutcheon JN, Javaid A, Giaccone G, Marshall JL and Wellstein A: Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer. Cancer Genet. 218–219. 39–50. 2017.
36	Zhang K, Zhou J, Zhu X, Luo M, Xu C, Yu J, Deng M, Zheng S and Chen Y: Germline mutations of PALB2 gene in a sequential series of Chinese patients with breast cancer. Breast Cancer Res Treat. 166:865–873. 2017. View Article : Google Scholar : PubMed/NCBI
37	Hayashi T, Yamashita T, Okada H, Nio K, Hara Y, Nomura Y, Hayashi T, Asahina Y, Yoshida M, Oishi N, et al: Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma. Cancer Cell Int. 17:942017. View Article : Google Scholar : PubMed/NCBI
38	Jiao J, Niu W, Wang Y, Baggerly K, Ye Y, Wu X, Davenport D, Almeda JL, Betancourt-Garcia MM, Forse RA, et al: Prevalence of Aflatoxin-associated TP53R249S mutation in hepatocellular carcinoma in hispanics in South texas. Cancer Prev Res (Phila). 11:103–112. 2018. View Article : Google Scholar : PubMed/NCBI
39	Riordan JD, Feddersen CR, Tschida BR, Beckmann PJ, Keng VW, Linden MA, Amin K, Stipp CS, Largaespada DA and Dupuy AJ: Chronic liver injury alters driver mutation profiles in hepatocellular carcinoma in mice. Hepatology. 67:924–939. 2018. View Article : Google Scholar : PubMed/NCBI
40	Tommasi S and Besaratinia A: A versatile assay for detection of aberrant DNA methylation in bladder cancer. Methods Mol Biol. 1655:29–41. 2018. View Article : Google Scholar : PubMed/NCBI