As a Potential Prognostic and Therapeutic Biomarker by Affecting Tumor Development and Immune Microenvironment in Hepatocellular Carcinoma

Overview

Journal Transl Cancer Res

Specialty Oncology

Date 2022 Sep 12

PMID 36093522

Authors

Zhibo Tan

Min Chen

Feng Peng

Pengfei Yang

Zhaoming Peng

Zhe Zhang

Xin Li

Xiaopeng Zhu

Lei Zhang

Yujie Zhao

Yajie Liu

Affiliations

Soon will be listed here.

Abstract

Background: plays a crucial role in cell cycle regulation. However, the exact role of in liver hepatocellular carcinoma (LIHC) remains controversial. This study aimed to integrate disparate data by bioinformatics for a deeper insight into the possible roles of in LIHC.

Methods: Differentially overexpressed genes in LIHC were screened by GEO2R. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were analyzed by WebGestalt. Then, hub genes were selected via STRING and Cytoscape, followed by validation with Oncomine, GEPIA2, and Human Protein Atlas (HPA). Next, expression was investigated using Oncomine, GEPIA2, TIMER2.0, UALCAN, and HPA. Then, Kaplan-Meier plotter was adopted to investigate survival. After that, promotor methylation, mutations and copy number alterations were analyzed with UALCAN and cBioPortal. Moreover, competing endogenous RNAs (ceRNAs) network were established using ENCORI, miRCancer, and Kaplan-Meier plotter. Additionally, the association between and immune microenvironment was investigated through TISCH and TIMER2.0.

Results: Six hub genes including were identified. was overexpressed in most solid cancers including LIHC. overexpression was correlated with poor prognosis in LIHC. Copy number alterations could positively affect expression. Moreover, ceRNAs network was established with 3 long non-coding RNAs (lncRNAs) named AC025048.4, AC090114.2, and AC092171.5, as well as 4 microRNAs (miRNAs) including miR-150-5p, miR-302c-3p, miR-520d-3p, and miR-330-5p. Single cell sequencing data showed that was mainly expressed in malignant cells and proliferating T cells, and that E2F targets almost exclusively enriched in proliferating T cells. Besides, there existed a positive correlation between and certain immune cells including CD8(+) T cells, CD4(+) T cells, B cells, macrophages, and dendritic cells.

Conclusions: This study elucidated that could affect tumor development and immune microenvironment in LIHC. Thus, might be a potential prognostic biomarker and therapeutic target for LIHC.

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References

Ladu S, Calvisi D, Conner E, Farina M, Factor V, Thorgeirsson S . E2F1 inhibits c-Myc-driven apoptosis via PIK3CA/Akt/mTOR and COX-2 in a mouse model of human liver cancer. Gastroenterology. 2008; 135(4):1322-32. PMC: 2614075. DOI: 10.1053/j.gastro.2008.07.012. View

Khan A, Liu Z, Xu X . Recent advances in immunotherapy for hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2021; 20(6):511-520. DOI: 10.1016/j.hbpd.2021.06.010. View

Xie X, Wang Y, Zhang S, Li J, Yu Z, Ding X . A novel five-lncRNA signature panel improves high-risk survival prediction in patients with cholangiocarcinoma. Aging (Albany NY). 2021; 13(2):2959-2981. PMC: 7880389. DOI: 10.18632/aging.202446. View

Huang Y, Ning G, Chen L, Lian Y, Gu Y, Wang J . Promising diagnostic and prognostic value of E2Fs in human hepatocellular carcinoma. Cancer Manag Res. 2019; 11:1725-1740. PMC: 6388971. DOI: 10.2147/CMAR.S182001. View

Chen Y, Wang T, Hsu H, Yuan R, Jeng Y . Overexpression of CTHRC1 in hepatocellular carcinoma promotes tumor invasion and predicts poor prognosis. PLoS One. 2013; 8(7):e70324. PMC: 3726622. DOI: 10.1371/journal.pone.0070324. View

Llovet J, Kelley R, Villanueva A, Singal A, Pikarsky E, Roayaie S . Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 7(1):6. DOI: 10.1038/s41572-020-00240-3. View

Kent L, Bae S, Tsai S, Tang X, Srivastava A, Koivisto C . Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma. J Clin Invest. 2017; 127(3):830-842. PMC: 5330731. DOI: 10.1172/JCI87583. View

Yang L, Guo Y, Liu X, Wang T, Tong X, Lei K . The tumor suppressive miR-302c-3p inhibits migration and invasion of hepatocellular carcinoma cells by targeting TRAF4. J Cancer. 2018; 9(15):2693-2701. PMC: 6072805. DOI: 10.7150/jca.25569. View

Llovet J, Montal R, Sia D, Finn R . Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018; 15(10):599-616. DOI: 10.1038/s41571-018-0073-4. View

10.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

11.

Fernandez-Barrena M, Arechederra M, Colyn L, Berasain C, Avila M . Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg. JHEP Rep. 2020; 2(6):100167. PMC: 7585149. DOI: 10.1016/j.jhepr.2020.100167. View

12.

Raja A, Haq F . Molecular classification of hepatocellular carcinoma: prognostic importance and clinical applications. J Cancer Res Clin Oncol. 2021; 148(1):15-29. DOI: 10.1007/s00432-021-03826-w. View

13.

Gao S, Zheng Q, Xu B, Pan C, Li K, Zhao Y . EZH2 represses target genes through H3K27-dependent and H3K27-independent mechanisms in hepatocellular carcinoma. Mol Cancer Res. 2014; 12(10):1388-97. DOI: 10.1158/1541-7786.MCR-14-0034. View

14.

He Z, Zhang S, Ma D, Fang Q, Yang L, Shen S . HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia. J Transl Med. 2019; 17(1):366. PMC: 6849246. DOI: 10.1186/s12967-019-2115-9. View

15.

Singal A, Lampertico P, Nahon P . Epidemiology and surveillance for hepatocellular carcinoma: New trends. J Hepatol. 2020; 72(2):250-261. PMC: 6986771. DOI: 10.1016/j.jhep.2019.08.025. View

16.

Edgar R, Domrachev M, Lash A . Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2001; 30(1):207-10. PMC: 99122. DOI: 10.1093/nar/30.1.207. View

17.

Wei C, Liang Q, Li X, Li H, Liu Y, Huang X . Bioinformatics profiling utilized a nine immune-related long noncoding RNA signature as a prognostic target for pancreatic cancer. J Cell Biochem. 2019; 120(9):14916-14927. DOI: 10.1002/jcb.28754. View

18.

Zhang C, Cui Y, Wang G, Zhao W, Zhao H, Huang X . Comprehensive Analysis of the Expression and Prognosis for E2Fs in Human Clear Cell Renal Cell Carcinoma. J Healthc Eng. 2021; 2021:5790416. PMC: 8440094. DOI: 10.1155/2021/5790416. View

19.

Liao Y, Wang J, Jaehnig E, Shi Z, Zhang B . WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 2019; 47(W1):W199-W205. PMC: 6602449. DOI: 10.1093/nar/gkz401. View

20.

Morgunova E, Yin Y, Jolma A, Dave K, Schmierer B, Popov A . Structural insights into the DNA-binding specificity of E2F family transcription factors. Nat Commun. 2015; 6:10050. PMC: 4686757. DOI: 10.1038/ncomms10050. View