Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Integrative Multi-Omics Analysis of Identified Ferroptosis-Marker RPL8 as a Candidate Oncogene Correlates with Poor Prognosis and Immune Infiltration in Liver Cancer

Author(s): Shunli Fan, Sai Zhang, Dejun Kong, Hao Wang, Yuan Shi, Zhenglu Wang and Hong Zheng*

Volume 26, Issue 7, 2023

Published on: 12 October, 2022

Page: [1298 - 1310] Pages: 13

DOI: 10.2174/1386207325666220823122942

Price: $65

Abstract

Background: Liver Hepatocellular Carcinoma (LIHC) is characterized by high malignancy, poor prognosis, and high recurrence rate worldwide. The role of ferroptosis in tumorigenesis and progression has been confirmed in previous studies. However, the multi-omics analysis in liver cancer of ferroptosis-markers RPL8 remains to be elucidated.

Methods: In this analysis, the RPL8 mRNA expression was analyzed via the GEPIA, TIMER and UALCAN databases. In addition, we verified the mRNA expression of RPL8 by qRT-PCR experiment. The Kaplan-Meier plotter, UALCAN, TCGAportal and HPA databases were applied to evaluate RPL8 on prognosis and clinicopathological parameters. Moreover, we used TIMER and Kaplan-Meier plotter to analyze the correlation of RPL8 to immune cell infiltration and immune cell type markers to prognosis. In addition, networks and function enrichment between RPL8 coexpression genes were analyzed by GeneMANIA, cBioportal and Metascape databases. What’s more, we used FerrDb and GEPIA databases to analyze the correlation of 23 Ferroptosis-related genes with RPL8.

Results: The mRNA expression of RPL8 was over-expressed in multiple cancers. In addition, transcription and translation levels of RPL8 in LIHC were significantly higher than normal tissues. Furthermore, higher expression of RPL8 was closely related to shorter OS in LIHC patients. The analysis of Kaplan-Meier plotter proved that RPL8 expression was related to stage, Sorafenib treatment, alcohol consumption and hepatitis virus. Moreover, the results showed that the methylation expression level of RPL8 was significantly associated with age, gender, grade, stage and TP53 mutation of LIHC. RPL8 and its co-expression genes were primarily involved in liver regeneration and immune system process. Immune infiltration analysis showed the RPL8 expression had positively correlated with immune cells and immune subtypes in LIHC. Furthermore, qRT-PCR experiment validated the expression difference of RPL8 in liver cancer.

Conclusion: Our findings elucidated that ferroptosis-markers RPL8 may play an important role in prognosis, and significantly correlate with ferroptosis-related genes, it also revealed the potential of RPL8 as a novel therapeutic target for LIHC treatment and prognosis assessment.

Keywords: liver cancer, RPL8, prognosis, immune infiltration, multi-omics.

« Previous Next »
Graphical Abstract

[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Jiang, Y-L.; Shang, M-M.; Dong, S-Z.; Chang, Y-C. Abnormally expressed circular RNAs as novel non-invasive biomarkers for hepatocellular carcinoma: A meta-analysis. World J. Gastrointest. Oncol., 2019, 11(10), 909-924.
[http://dx.doi.org/10.4251/wjgo.v11.i10.909] [PMID: 31662829]
[3]
Huang, Y-L.; Ning, G.; Chen, L-B.; Lian, Y-F.; Gu, Y-R.; Wang, J-L.; Chen, D-M.; Wei, H.; Huang, Y-H. Promising diagnostic and prognostic value of E2Fs in human hepatocellular carcinoma. Cancer Manag. Res., 2019, 11, 1725-1740.
[http://dx.doi.org/10.2147/CMAR.S182001] [PMID: 30863181]
[4]
Stockwell, B.R.; Friedmann Angeli, J.P.; Bayir, H.; Bush, A.I.; Conrad, M.; Dixon, S.J.; Fulda, S.; Gascón, S.; Hatzios, S.K.; Kagan, V.E.; Noel, K.; Jiang, X.; Linkermann, A.; Murphy, M.E.; Overholtzer, M.; Oyagi, A.; Pagnussat, G.C.; Park, J.; Ran, Q.; Rosenfeld, C.S.; Salnikow, K.; Tang, D.; Torti, F.M.; Torti, S.V.; Toyokuni, S.; Woerpel, K.A.; Zhang, D.D. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell, 2017, 171(2), 273-285.
[http://dx.doi.org/10.1016/j.cell.2017.09.021] [PMID: 28985560]
[5]
Louandre, C.; Marcq, I.; Bouhlal, H.; Lachaier, E.; Godin, C.; Saidak, Z.; François, C.; Chatelain, D.; Debuysscher, V.; Barbare, J.C.; Chauffert, B.; Galmiche, A. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett., 2015, 356(2 Pt B), 971-977.
[http://dx.doi.org/10.1016/j.canlet.2014.11.014] [PMID: 25444922]
[6]
Sun, X.; Niu, X.; Chen, R.; He, W.; Chen, D.; Kang, R.; Tang, D. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology, 2016, 64(2), 488-500.
[http://dx.doi.org/10.1002/hep.28574] [PMID: 27015352]
[7]
Sun, X.; Ou, Z.; Chen, R.; Niu, X.; Chen, D.; Kang, R.; Tang, D. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology, 2016, 63(1), 173-184.
[http://dx.doi.org/10.1002/hep.28251] [PMID: 26403645]
[8]
Yuan, H.; Li, X.; Zhang, X.; Kang, R.; Tang, D. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem. Biophys. Res. Commun., 2016, 478(2), 838-844.
[http://dx.doi.org/10.1016/j.bbrc.2016.08.034] [PMID: 27510639]
[9]
Sun, J.; Zhou, C.; Zhao, Y.; Zhang, X.; Chen, W.; Zhou, Q.; Hu, B.; Gao, D.; Raatz, L.; Wang, Z.; Nelson, P.J.; Jiang, Y.; Ren, N.; Bruns, C.J.; Zhou, H. Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation. Redox Biol., 2021, 41, 101942.
[http://dx.doi.org/10.1016/j.redox.2021.101942] [PMID: 33770521]
[10]
Wang, Q.; Bin, C.; Xue, Q.; Gao, Q.; Huang, A.; Wang, K.; Tang, N. GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. Cell Death Dis., 2021, 12(5), 426.
[http://dx.doi.org/10.1038/s41419-021-03718-4] [PMID: 33931597]
[11]
Hanes, J.; Klaudiny, J.; von der Kammer, H.; Scheit, K.H. Characterization by cDNA cloning of the mRNA of human ribosomal protein L8. Biochem. Biophys. Res. Commun., 1993, 197(3), 1223-1228.
[http://dx.doi.org/10.1006/bbrc.1993.2607] [PMID: 7506540]
[12]
Futschik, M.; Jeffs, A.; Pattison, S.; Kasabov, N.; Sullivan, M.; Merrie, A.; Reeve, A. Gene expression profiling of metastatic and nonmetastatic colorectal cancer cell lines. Genome Lett., 2002, 1(1), 26-34.
[http://dx.doi.org/10.1166/gl.2002.005]
[13]
Park, J.M.; Mau, C.Z.; Chen, Y.C.; Su, Y.H.; Chen, H.A.; Huang, S.Y.; Chang, J.S.; Chiu, C.F. A case-control study in Taiwanese cohort and meta-analysis of serum ferritin in pancreatic cancer. Sci. Rep., 2021, 11(1), 21242.
[http://dx.doi.org/10.1038/s41598-021-00650-7] [PMID: 34711879]
[14]
Maharjan, R.S.; Singh, A.V.; Hanif, J.; Rosenkranz, D.; Haidar, R.; Shelar, A.; Singh, S.P.; Dey, A.; Patil, R.; Zamboni, P.; Laux, P.; Luch, A. Investigation of the associations between a nanomaterial’s microrheology and toxicology. ACS Omega, 2022, 7(16), 13985-13997.
[http://dx.doi.org/10.1021/acsomega.2c00472] [PMID: 35559161]
[15]
Shinawi, T.; Hill, V.K.; Krex, D.; Schackert, G.; Gentle, D.; Morris, M.R.; Wei, W.; Cruickshank, G.; Maher, E.R.; Latif, F. DNA methylation profiles of long- and short-term glioblastoma survivors. Epigenetics, 2013, 8(2), 149-156.
[http://dx.doi.org/10.4161/epi.23398] [PMID: 23291739]
[16]
Men, C.; Chai, H.; Song, X.; Li, Y.; Du, H.; Ren, Q. Identification of DNA methylation associated gene signatures in endometrial cancer via integrated analysis of DNA methylation and gene expression systematically. J. Gynecol. Oncol., 2017, 28(6), e83.
[http://dx.doi.org/10.3802/jgo.2017.28.e83] [PMID: 29027401]
[17]
Forner, A.; Reig, M.; Bruix, J. Hepatocellular carcinoma. Lancet, 2018, 391(10127), 1301-1314.
[http://dx.doi.org/10.1016/S0140-6736(18)30010-2] [PMID: 29307467]
[18]
Yang, W.S.; Kim, K.J.; Gaschler, M.M.; Patel, M.; Shchepinov, M.S.; Stockwell, B.R. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc. Natl. Acad. Sci. USA, 2016, 113(34), E4966-E4975.
[http://dx.doi.org/10.1073/pnas.1603244113] [PMID: 27506793]
[19]
Hou, L.; Huang, R.; Sun, F.; Zhang, L.; Wang, Q. NADPH oxidase regulates paraquat and maneb-induced dopaminergic neurodegeneration through ferroptosis. Toxicology, 2019, 417, 64-73.
[http://dx.doi.org/10.1016/j.tox.2019.02.011] [PMID: 30797899]
[20]
Gao, M.; Monian, P.; Quadri, N.; Ramasamy, R.; Jiang, X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell, 2015, 59(2), 298-308.
[http://dx.doi.org/10.1016/j.molcel.2015.06.011] [PMID: 26166707]
[21]
Liu, Y.; Zhu, X.; Zhu, J.; Liao, S.; Tang, Q.; Liu, K.; Guan, X.; Zhang, J.; Feng, Z. Identification of differential expression of genes in hepatocellular carcinoma by suppression subtractive hybridization combined cDNA microarray. Oncol. Rep., 2007, 18(4), 943-951.
[http://dx.doi.org/10.3892/or.18.4.943] [PMID: 17786358]
[22]
Walraven, M.; Sabrkhany, S.; Knol, J.C.; Dekker, H.; de Reus, I.; Piersma, S.R.; Pham, T.V.; Griffioen, A.W.; Broxterman, H.J.; Oude Egbrink, M.; Verheul, H.M.W.; Jimenez, C.R. Effects of cancer presence and therapy on the platelet proteome. Int. J. Mol. Sci., 2021, 22(15), 22.
[http://dx.doi.org/10.3390/ijms22158236] [PMID: 34361002]
[23]
Zhang, Y.; Zhang, J.; Chen, X.; Yang, Z. Polymeric immunoglobulin receptor (PIGR) exerts oncogenic functions via activating ribosome pathway in hepatocellular carcinoma. Int. J. Med. Sci., 2021, 18(2), 364-371.
[http://dx.doi.org/10.7150/ijms.49790] [PMID: 33390805]
[24]
Tawa, G.J.; Braisted, J.; Gerhold, D.; Grewal, G.; Mazcko, C.; Breen, M.; Sittampalam, G.; LeBlanc, A.K. Transcriptomic profiling in canines and humans reveals cancer specific gene modules and biological mechanisms common to both species. PLOS Comput. Biol., 2021, 17(9), e1009450.
[http://dx.doi.org/10.1371/journal.pcbi.1009450] [PMID: 34570764]
[25]
Huang, W.; Duan, Y.; Yang, X.; Shang, C.; Chen, X.; Zhang, H.; Li, F. Identification of novel prognostic risk signatures of soft tissue sarcoma based on ferroptosis-related genes. Front. Oncol., 2021, 11, 629868.
[http://dx.doi.org/10.3389/fonc.2021.629868] [PMID: 33889544]
[26]
Sun, L.; Li, J.; Yan, B. Gene expression profiling analysis of osteosarcoma cell lines. Mol. Med. Rep., 2015, 12(3), 4266-4272.
[http://dx.doi.org/10.3892/mmr.2015.3958] [PMID: 26096802]
[27]
Zhou, M.; Zhang, X.; Li, T.; Chen, Y. Dysregulated ferroptosis-related genes indicate potential clinical benefits for anti-PD-1/PD-L1 immunotherapy in lung adenocarcinoma. J. Clin. Lab. Anal., 2021, 35(12), e24086.
[http://dx.doi.org/10.1002/jcla.24086] [PMID: 34752672]
[28]
Zhao, Y.Y.; Lian, J.X.; Lan, Z.; Zou, K.L.; Wang, W.M.; Yu, G.T. Ferroptosis promotes anti-tumor immune response by inducing immunogenic exposure in HNSCC. Oral Dis., 2021, odi.14077.
[http://dx.doi.org/10.1111/odi.14077] [PMID: 34773344]
[29]
Lei, T.; Qian, H.; Lei, P.; Hu, Y. Ferroptosis-related gene signature associates with immunity and predicts prognosis accurately in patients with osteosarcoma. Cancer Sci., 2021, 112(11), 4785-4798.
[http://dx.doi.org/10.1111/cas.15131] [PMID: 34506683]
[30]
Han, L.; Bai, L.; Qu, C.; Dai, E.; Liu, J.; Kang, R.; Zhou, D.; Tang, D.; Zhao, Y. PPARG-mediated ferroptosis in dendritic cells limits antitumor immunity. Biochem. Biophys. Res. Commun., 2021, 576, 33-39.
[http://dx.doi.org/10.1016/j.bbrc.2021.08.082] [PMID: 34478917]
[31]
Swoboda, R.K.; Somasundaram, R.; Caputo, L.; Ochoa, E.M.; Gimotty, P.A.; Marincola, F.M.; Van Belle, P.; Barth, S.; Elder, D.; Guerry, D.; Czerniecki, B.; Schuchter, L.; Vonderheide, R.H.; Herlyn, D. Shared MHC class II-dependent melanoma ribosomal protein L8 identified by phage display. Cancer Res., 2007, 67(8), 3555-3559.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-2763] [PMID: 17440064]
[32]
Zhang, H.X.; Liu, Z.X.; Sun, Y.P.; Zhu, J.; Lu, S.Y.; Liu, X.S.; Huang, Q.H.; Xie, Y.Y.; Zhu, H.B.; Dang, S.Y.; Chen, H.F.; Zheng, G.Y.; Li, Y.X.; Kuang, Y.; Fei, J.; Chen, S.J.; Chen, Z.; Wang, Z.G. Rig-I regulates NF-κB activity through binding to Nf-κb1 3′-UTR mRNA. Proc. Natl. Acad. Sci. USA, 2013, 110.
[http://dx.doi.org/10.1073/pnas.1304432110]
[33]
Chen, X.; Hou, H.; Qiao, H.; Fan, H.; Zhao, T.; Dong, M. Identification of blood-derived candidate gene markers and a new 7-gene diagnostic model for multiple sclerosis. Biol. Res., 2021, 54(1), 12.
[http://dx.doi.org/10.1186/s40659-021-00334-6] [PMID: 33795012]
[34]
Tsai, T-J.; Chao, W-Y.; Chen, C-C.; Chen, Y-J.; Lin, C-Y.; Lee, Y-R. Gelsolin-like actin-capping protein (CapG) overexpression in the cytoplasm of human hepatocellular carcinoma, associated with cellular invasion, migration and tumor prognosis. Anticancer Res., 2018, 38(7), 3943-3950.
[http://dx.doi.org/10.21873/anticanres.12680] [PMID: 29970516]
[35]
Kimura, K.; Ojima, H.; Kubota, D.; Sakumoto, M.; Nakamura, Y.; Tomonaga, T.; Kosuge, T.; Kondo, T. Proteomic identification of the macrophage-capping protein as a protein contributing to the malignant features of hepatocellular carcinoma. J. Proteomics, 2013, 78, 362-373.
[http://dx.doi.org/10.1016/j.jprot.2012.10.004] [PMID: 23085225]
[36]
Nakamura, M.; Kitaura, J.; Enomoto, Y.; Lu, Y.; Nishimura, K.; Isobe, M.; Ozaki, K.; Komeno, Y.; Nakahara, F.; Oki, T.; Kume, H.; Homma, Y.; Kitamura, T. Transforming growth factor-β-stimulated clone-22 is a negative-feedback regulator of Ras / Raf signaling: Implications for tumorigenesis. Cancer Sci., 2012, 103(1), 26-33.
[http://dx.doi.org/10.1111/j.1349-7006.2011.02108.x] [PMID: 21943131]
[37]
Cai, P.; Zheng, H.; She, J.; Feng, N.; Zou, H.; Gu, J.; Yuan, Y.; Liu, X.; Liu, Z.; Bian, J. Molecular mechanism of aflatoxin-induced hepatocellular carcinoma derived from a bioinformatics analysis. Toxins (Basel), 2020, 12(3), 12.
[http://dx.doi.org/10.3390/toxins12030203] [PMID: 32210020]
[38]
Chen, Y.L.; Chan, S.H.; Lin, P.Y.; Chu, P.Y. The expression of a tumor suppressor gene JDP2 and its prognostic value in hepatocellular carcinoma patients. Hum. Pathol., 2017, 63, 212-216.
[http://dx.doi.org/10.1016/j.humpath.2017.03.003] [PMID: 28315425]
[39]
Cho, S.Y.; Kim, S.; Son, M.J.; Rou, W.S.; Kim, S.H.; Eun, H.S.; Lee, B.S. Clinical significance of the thioredoxin system and thioredoxin-domain-containing protein family in hepatocellular carcinoma. Dig. Dis. Sci., 2019, 64(1), 123-136.
[http://dx.doi.org/10.1007/s10620-018-5307-x] [PMID: 30288659]
[40]
Li, J.; Yue, Z.; Xiong, W.; Sun, P.; You, K.; Wang, J. TXNIP overexpression suppresses proliferation and induces apoptosis in SMMC7221 cells through ROS generation and MAPK pathway activation. Oncol. Rep., 2017, 37(6), 3369-3376.
[http://dx.doi.org/10.3892/or.2017.5577] [PMID: 28440491]
[41]
Zhang, Y.; Yan, Q.; Gong, L.; Xu, H.; Liu, B.; Fang, X.; Yu, D.; Li, L.; Wei, T.; Wang, Y.; Wong, C.N.; Lyu, Z.; Tang, Y.; Sham, P.C.; Guan, X.Y. C-terminal truncated HBx initiates hepatocarcinogenesis by downregulating TXNIP and reprogramming glucose metabolism. Oncogene, 2021, 40(6), 40.
[http://dx.doi.org/10.1038/s41388-020-01593-5]
[42]
Xu, P.; Oosterveer, M.H.; Stein, S.; Demagny, H.; Ryu, D.; Moullan, N.; Wang, X.; Can, E.; Zamboni, N.; Comment, A.; Auwerx, J.; Schoonjans, K. LRH-1-dependent programming of mitochondrial glutamine processing drives liver cancer. Genes Dev., 2016, 30(11), 1255-1260.
[http://dx.doi.org/10.1101/gad.277483.116] [PMID: 27298334]

Rights & Permissions Print Cite
Article Metrics
3
© 2024 Bentham Science Publishers | Privacy Policy