Establishment of a Prognostic Model for Hepatocellular Carcinoma Based on Bioinformatics and the Role of NR6A1 in the Progression of HCC

Overview

Journal J Clin Transl Hepatol

Specialty Gastroenterology

Date 2022 Oct 28

PMID 36304495

Authors

Zhong-Hua Lin

Jie Zhang

Li-Kun Zhuang

Yong-Ning Xin

Shi-Ying Xuan

Affiliations

Soon will be listed here.

Abstract

Background And Aims: Generally acceptable prognostic models for hepatocellular carcinoma (HCC) are not available. This study aimed to establish a prognostic model for HCC by identifying immune-related differentially expressed genes (IR-DEGs) and to investigate the potential role of in the progression of HCC.

Methods: Bioinformatics analysis using The Cancer Genome Atlas and ImmPort databases was used to identify IR-DEGs. Lasso Cox regression and multivariate Cox regression analysis were used to establish a prognostic model of HCC. Kaplan-Meier analysis and the receiver operating characteristic (ROC) curves were used to evaluate the performance of the prognostic model, which was further verified in the International Cancer Genome Consortium (ICGC) database. Gene set enrichment analysis was used to explore the potential pathways of . Cell counting kit 8, colony formation, wound healing, and Transwell migration assays using Huh7 cells, and tumor formation models in nude mice were conducted.

Results: A prognostic model established based on ten identified IR-DEGs including and , effectively predicted the prognosis of HCC patients, was confirmed by the ROC curves and verified in ICGC database. expression was significantly up-regulated in HCC patients, and was significantly associated with a low survival rate. Gene set enrichment analysis showed the enrichment of cell cycle, mTOR, WNT, and ERBB signaling pathways in patients with high expression. promoted cell proliferation, invasiveness, migration, and malignant tumor formation and growth and .

Conclusions: An effective prognostic model for HCC, based on a novel signature of 10 immune-related genes, was established. was up-regulated in HCC and was associated with a poor prognosis of HCC. promoted cell proliferation, migration, and growth of HCC, most likely through the cell cycle, mTOR, WNT, and ERBB signaling pathways.

Citing Articles

Transcriptomic-Based Identification of miR-125a Novel Targets in Human Hepatocarcinoma Cells.

De Leo I, Mosca N, Pezzullo M, Valletta D, Manfrevola F, Mele V Biomolecules. 2025; 15(1).

PMID: 39858538 PMC: 11763984. DOI: 10.3390/biom15010144.

Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma.

Wu Q, Li X, Long M, Xie X, Liu Q Sci Rep. 2023; 13(1):18642.

PMID: 37903971 PMC: 10616101. DOI: 10.1038/s41598-023-46057-4.

[EHHADH is a key gene in fatty acid metabolism pathways in hepatocellular carcinoma: a transcriptomic analysis].

Xie S, Li M, Jiang F, Yi Q, Yang W Nan Fang Yi Ke Da Xue Xue Bao. 2023; 43(5):680-693.

PMID: 37313808 PMC: 10267234. DOI: 10.12122/j.issn.1673-4254.2023.05.02.

References

Ghavimi S, Apfel T, Azimi H, Persaud A, Pyrsopoulos N . Management and Treatment of Hepatocellular Carcinoma with Immunotherapy: A Review of Current and Future Options. J Clin Transl Hepatol. 2020; 8(2):168-176. PMC: 7438354. DOI: 10.14218/JCTH.2020.00001. View

Ma C, Xu T, Sun X, Zhang S, Liu S, Fan S . Network Pharmacology and Bioinformatics Approach Reveals the Therapeutic Mechanism of Action of Baicalein in Hepatocellular Carcinoma. Evid Based Complement Alternat Med. 2019; 2019:7518374. PMC: 6390240. DOI: 10.1155/2019/7518374. View

Wang B, Lan T, Xiao H, Chen Z, Wei C, Chen L . The expression profiles and prognostic values of HSP70s in hepatocellular carcinoma. Cancer Cell Int. 2021; 21(1):286. PMC: 8165812. DOI: 10.1186/s12935-021-01987-9. View

Wang Y, Wan X, Hao Y, Zhao Y, Du L, Huang Y . NR6A1 regulates lipid metabolism through mammalian target of rapamycin complex 1 in HepG2 cells. Cell Commun Signal. 2019; 17(1):77. PMC: 6637573. DOI: 10.1186/s12964-019-0389-4. View

Huang J, Liu S, Ma H, Yang Y, Zhang X, Sun H . Systematic Review and Meta-Analysis: Circulating miRNAs for Diagnosis of Hepatocellular Carcinoma. J Cell Physiol. 2015; 231(2):328-35. DOI: 10.1002/jcp.25135. View

Mikawa S, Morozumi T, Shimanuki S, Hayashi T, Uenishi H, Domukai M . Fine mapping of a swine quantitative trait locus for number of vertebrae and analysis of an orphan nuclear receptor, germ cell nuclear factor (NR6A1). Genome Res. 2007; 17(5):586-93. PMC: 1855175. DOI: 10.1101/gr.6085507. View

Casadei-Gardini A, Orsi G, Caputo F, Ercolani G . Developments in predictive biomarkers for hepatocellular carcinoma therapy. Expert Rev Anticancer Ther. 2020; 20(1):63-74. DOI: 10.1080/14737140.2020.1712198. View

Wang Y, Zhang Y, Dai X, Liu Z, Yin P, Wang N . NR6A1 couples with cAMP response element binding protein and regulates vascular smooth muscle cell migration. Int J Biochem Cell Biol. 2015; 69:225-32. DOI: 10.1016/j.biocel.2015.10.026. View

Conesa A, Madrigal P, Tarazona S, Gomez-Cabrero D, Cervera A, McPherson A . A survey of best practices for RNA-seq data analysis. Genome Biol. 2016; 17:13. PMC: 4728800. DOI: 10.1186/s13059-016-0881-8. View

10.

Hernandez-Gea V, Toffanin S, Friedman S, Llovet J . Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013; 144(3):512-27. PMC: 3578068. DOI: 10.1053/j.gastro.2013.01.002. View

11.

Bertino G, Demma S, Ardiri A, Proiti M, Mangia A, Gruttadauria S . The immune system in hepatocellular carcinoma and potential new immunotherapeutic strategies. Biomed Res Int. 2015; 2015:731469. PMC: 4393929. DOI: 10.1155/2015/731469. View

12.

CHUNG A, Cooney A . Germ cell nuclear factor. Int J Biochem Cell Biol. 2001; 33(12):1141-6. DOI: 10.1016/s1357-2725(01)00081-4. View

13.

Lu W, Chua M, So S . Suppressing N-Myc downstream regulated gene 1 reactivates senescence signaling and inhibits tumor growth in hepatocellular carcinoma. Carcinogenesis. 2013; 35(4):915-22. PMC: 4335260. DOI: 10.1093/carcin/bgt401. View

14.

Cheng G, Wang S, Li X, Li S, Zheng Y, Zhang L . Positive expression of NR6A1/CT150 as a predictor of biochemical recurrence-free survival in prostate cancer patients. Oncotarget. 2017; 8(38):64427-64439. PMC: 5610014. DOI: 10.18632/oncotarget.11749. View

15.

Giovangrandi Y, Parfait B, Asheuer M, Olivi M, Lidereau R, Vidaud M . Analysis of the human CGB/LHB gene cluster in breast tumors by real-time quantitative RT-PCR assays. Cancer Lett. 2001; 168(1):93-100. DOI: 10.1016/s0304-3835(01)00496-7. View

16.

Chang H, Nuyten D, Sneddon J, Hastie T, Tibshirani R, Sorlie T . Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci U S A. 2005; 102(10):3738-43. PMC: 548329. DOI: 10.1073/pnas.0409462102. View

17.

Sun X, Wang M, Zhang F, Kong X . An integrated analysis of genome-wide DNA methylation and gene expression data in hepatocellular carcinoma. FEBS Open Bio. 2018; 8(7):1093-1103. PMC: 6026698. DOI: 10.1002/2211-5463.12433. View

18.

Kang Y, Jeong E, Seok H, Kim S, Hwang J, Choi M . Cks1 regulates human hepatocellular carcinoma cell progression through osteopontin expression. Biochem Biophys Res Commun. 2018; 508(1):275-281. DOI: 10.1016/j.bbrc.2018.11.070. View

19.

Qu X, Othus M, Davison J, Wu Y, Yan L, Meshinchi S . Prognostic methylation markers for overall survival in cytogenetically normal patients with acute myeloid leukemia treated on SWOG trials. Cancer. 2017; 123(13):2472-2481. PMC: 5705230. DOI: 10.1002/cncr.30626. View

20.

Xu G, Zhang M, Zhu H, Xu J . A 15-gene signature for prediction of colon cancer recurrence and prognosis based on SVM. Gene. 2016; 604:33-40. DOI: 10.1016/j.gene.2016.12.016. View