Identification of CLIC5 as a Prognostic Biomarker and Correlated
Immunomodulator for Lung Adenocarcinoma

Tingting      Bian; Wenyi      Zhang; Fengxu      Wang; Xiuyu      Chu; Xiaohui      Pan; Junpu      Ruan; Shali      Yu; Lei      Liu; Hui      Sun; Hongmei      Qiu; Ye      Li; Juan      Tang; Xinyuan      Zhao; Hongbing      Zhang

doi:10.2174/1386207326666230410103255

Abstract

Background: Lung adenocarcinoma (LUAD) is one of the most common pathological types of lung cancer. The gene Chloride Intracellular Channel 5 (CLIC5) has an important role in neurophysiology, cardiovascular biology, and tumour biology. Here, we explored the prognostic value and immune infiltration of CLIC5 expression in LUAD patients.

Methods: We extracted transcriptional LUAD data from The Cancer Genome Atlas (TCGA) and the University of Alabama Cancer Database to explore CLIC5 expression profiles and their relation to CLIC5 and clinicopathological parameters. The relationship between CLIC5 and survival time was explored using Kaplan-Meier Plotter. Then, we integrated the data from TCGA and the Gene Expression Omnibus (GEO) database to perform univariate and multivariate Cox regression. We performed CLIC5 immunohistochemical staining on 167 lung adenocarcinoma samples for further verification. In addition, we analysed the Gene Ontology (GO) database, Kyoto Encyclopaedia of Genes and Genomes pathways and network analysis of protein-protein interactions in lung tissue, to explore the potential mechanism of CLIC5. To analyse the correlation between immune infiltration and CLIC5 expression, we first compared the expression of immune cells in tumour tissues and normal tissues based on the TCGA and GEO databases. We found 51 immunomodulators related to CLIC5 and structured their enrichment pathways as well as those of 50 correlated genes. We used a Cox regression model to identify multiple-gene risk prediction signatures. Finally, we assessed the prognostic accuracy of the risk scores via receiver operating characteristic curves.

Results: CLIC5 expression levels were significantly lower in LUAD tissue than in normal tissue. Lower CLIC5 expression was negatively correlated to the overall survival of LUAD patients based on survival analysis. We identified CLIC5 as an independent prognosis predictor. Functional network analysis suggested that CLIC5 is related to multiple pathways. CLIC5 expression is closely related to infiltration levels of many immune cells and immune marker sets in LUAD patients. Furthermore, the risk score based on immunomodulators related to CLIC5 was an independent prognosis predictor in the TCGA lung cohorts.

Conclusion: Our findings suggest that CLIC5 is a promising molecular marker for the prognosis and immune infiltration of LUAD patients.

« Previous Next »

Graphical Abstract

[1]
Zengin, T.; Onal-Süzek, T. Analysis of genomic and transcriptomic variations as prognostic signature for lung adenocarcinoma. BMC Bioinformatics,  2020, 21(S14), 368.
 [http://dx.doi.org/10.1186/s12859-020-03691-3] [PMID: 32998690]

[2]
Li, R.; Yang, Y.E.; Yin, Y.H.; Zhang, M.Y.; Li, H.; Qu, Y.Q. Methylation and transcriptome analysis reveal lung adenocarcinoma-specific diagnostic biomarkers. J. Transl. Med.,  2019, 17(1), 324.
 [http://dx.doi.org/10.1186/s12967-019-2068-z] [PMID: 31558162]

[3]
Liang, J.; Li, H.; Han, J.; Jiang, J.; Wang, J.; Li, Y.; Feng, Z.; Zhao, R.; Sun, Z.; Lv, B.; Tian, H. Mex3a interacts with LAMA2 to promote lung adenocarcinoma metastasis via PI3K/AKT pathway. Cell Death Dis.,  2020, 11(8), 614.
 [http://dx.doi.org/10.1038/s41419-020-02858-3] [PMID: 32792503]

[4]
Arneth, B. Tumor microenvironment. Medicina,  2019, 56(1), 15.
 [http://dx.doi.org/10.3390/medicina56010015] [PMID: 31906017]

[5]
Wu, T.; Dai, Y. Tumor microenvironment and therapeutic response. Cancer Lett.,  2017, 387, 61-68.
 [http://dx.doi.org/10.1016/j.canlet.2016.01.043] [PMID: 26845449]

[6]
Hinshaw, D.C.; Shevde, L.A. The tumor microenvironment innately modulates cancer progression. Cancer Res.,  2019, 79(18), 4557-4566.
 [http://dx.doi.org/10.1158/0008-5472.CAN-18-3962] [PMID: 31350295]

[7]
Gururaja Rao, S.; Patel, N.J.; Singh, H. Intracellular chloride channels: Novel biomarkers in diseases. Front. Physiol.,  2020, 11, 96.
 [http://dx.doi.org/10.3389/fphys.2020.00096] [PMID: 32116799]

[8]
Neveu, B.; Spinella, J.F.; Richer, C.; Lagacé, K.; Cassart, P.; Lajoie, M.; Jananji, S.; Drouin, S.; Healy, J.; Hickson, G.R.X.; Sinnett, D. CLIC5: A novel ETV6 target gene in childhood acute lymphoblastic leukemia. Haematologica,  2016, 101(12), 1534-1543.
 [http://dx.doi.org/10.3324/haematol.2016.149740] [PMID: 27540136]

[9]
Flores-Téllez, T.N.J.; Lopez, T.V.; Vásquez Garzón, V.R.; Villa-Treviño, S. Co-expression of Ezrin-CLIC5-podocalyxin is associated with migration and invasiveness in hepatocellular carcinoma. PLoS One,  2015, 10(7), e0131605.
 [http://dx.doi.org/10.1371/journal.pone.0131605] [PMID: 26135398]

[10]
Chandrashekar, D.S.; Bashel, B.; Balasubramanya, S.A.H.; Creighton, C.J.; Ponce-Rodriguez, I.; Chakravarthi, B.V.S.K.; Varambally, S. UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia,  2017, 19(8), 649-658.
 [http://dx.doi.org/10.1016/j.neo.2017.05.002] [PMID: 28732212]

[11]
Tomczak, K.; Czerwińska, P.; Wiznerowicz, M. Review The Cancer Genome Atlas (TCGA): An immeasurable source of knowledge. Contemp. Oncol.,  2015, 1A(1A), 68-77.
 [http://dx.doi.org/10.5114/wo.2014.47136] [PMID: 25691825]

[12]
Sun, C.C.; Li, S.J.; Hu, W.; Zhang, J.; Zhou, Q.; Liu, C.; Li, L.L.; Songyang, Y.Y.; Zhang, F.; Chen, Z.L.; Li, G.; Bi, Z.Y.; Bi, Y.Y.; Gong, F.Y.; Bo, T.; Yuan, Z.P.; Hu, W.D.; Zhan, B.T.; Zhang, Q.; He, Q.Q.; Li, D.J. Retracted: Comprehensive analysis of the expression and prognosis for E2Fs in human breast cancer. Mol. Ther.,  2019, 27(6), 1153-1165.
 [http://dx.doi.org/10.1016/j.ymthe.2019.03.019] [PMID: 31010740]

[13]
Liu, Y.; Xie, P.; Jiang, D.; Liu, J.; Zhang, J.; Bian, T.; Shi, J. Molecular and immune characteristics for lung adenocarcinoma patients with ERLIN2 overexpression. Front. Immunol.,  2020, 11, 568440.
 [http://dx.doi.org/10.3389/fimmu.2020.568440] [PMID: 33424830]

[14]
Vasaikar, S.V.; Straub, P.; Wang, J.; Zhang, B. LinkedOmics: Analyzing multi-omics data within and across 32 cancer types. Nucleic Acids Res.,  2018, 46(D1), D956-D963.
 [http://dx.doi.org/10.1093/nar/gkx1090] [PMID: 29136207]

[15]
Li, T.; Fan, J.; Wang, B.; Traugh, N.; Chen, Q.; Liu, J.S.; Li, B.; Liu, X.S. TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res.,  2017, 77(21), e108-e110.
 [http://dx.doi.org/10.1158/0008-5472.CAN-17-0307] [PMID: 29092952]

[16]
Cerami, E.; Gao, J.; Dogrusoz, U.; Gross, B.E.; Sumer, S.O.; Aksoy, B.A.; Jacobsen, A.; Byrne, C.J.; Heuer, M.L.; Larsson, E.; Antipin, Y.; Reva, B.; Goldberg, A.P.; Sander, C.; Schultz, N. The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov.,  2012, 2(5), 401-404.
 [http://dx.doi.org/10.1158/2159-8290.CD-12-0095] [PMID: 22588877]

[17]
Szklarczyk, D.; Gable, A.L.; Lyon, D.; Junge, A.; Wyder, S.; Huerta-Cepas, J.; Simonovic, M.; Doncheva, N.T.; Morris, J.H.; Bork, P.; Jensen, L.J.; Mering, C. STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res.,  2019, 47(D1), D607-D613.
 [http://dx.doi.org/10.1093/nar/gky1131] [PMID: 30476243]

[18]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res.,  2003, 13(11), 2498-2504.
 [http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]

[19]
Ru, B.; Wong, C.N.; Tong, Y.; Zhong, J.Y.; Zhong, S.S.W.; Wu, W.C.; Chu, K.C.; Wong, C.Y.; Lau, C.Y.; Chen, I.; Chan, N.W.; Zhang, J. TISIDB: An integrated repository portal for tumor–immune system interactions. Bioinformatics,  2019, 35(20), 4200-4202.
 [http://dx.doi.org/10.1093/bioinformatics/btz210] [PMID: 30903160]

[20]
Li, J.P.; Li, R.; Liu, X.; Huo, C.; Liu, T.T.; Yao, J.; Qu, Y.Q. A seven immune-related lncRNAs model to increase the predicted value of lung adenocarcinoma. Front. Oncol.,  2020, 10, 560779.
 [http://dx.doi.org/10.3389/fonc.2020.560779] [PMID: 33163400]

[21]
Xu, Z.; Zhao, M.; Chen, W.; Li, K.; Qin, F.; Xiang, W.; Sun, Y.; Wei, J.; Yuan, L.; Li, S.; Lin, S. Analysis of prognostic genes in the tumor microenvironment of lung adenocarcinoma. PeerJ,  2020, 8, e9530.
 [http://dx.doi.org/10.7717/peerj.9530] [PMID: 32775050]

[22]
Singh, H.; Cousin, M.A.; Ashley, R.H. Functional reconstitution of mammalian ‘chloride intracellular channels’ CLIC1, CLIC4 and CLIC5 reveals differential regulation by cytoskeletal actin. FEBS J.,  2007, 274(24), 6306-6316.
 [http://dx.doi.org/10.1111/j.1742-4658.2007.06145.x] [PMID: 18028448]

[23]
Yang, Y. Cancer immunotherapy: Harnessing the immune system to battle cancer. J. Clin. Invest.,  2015, 125(9), 3335-3337.
 [http://dx.doi.org/10.1172/JCI83871] [PMID: 26325031]

[24]
Liu, X.; Wu, S.; Yang, Y.; Zhao, M.; Zhu, G.; Hou, Z. The prognostic landscape of tumor-infiltrating immune cell and immunomodulators in lung cancer. Biomed. Pharmacother.,  2017, 95, 55-61.
 [http://dx.doi.org/10.1016/j.biopha.2017.08.003] [PMID: 28826097]

[25]
Constantino, J.; Gomes, C.; Falcão, A.; Neves, B.M.; Cruz, M.T. Dendritic cell-based immunotherapy: A basic review and recent advances. Immunol. Res.,  2017, 65(4), 798-810.
 [http://dx.doi.org/10.1007/s12026-017-8931-1] [PMID: 28660480]

[26]
Kishton, R.J.; Sukumar, M.; Restifo, N.P. Metabolic regulation of T cell longevity and function in tumor immunotherapy. Cell Metab.,  2017, 26(1), 94-109.
 [http://dx.doi.org/10.1016/j.cmet.2017.06.016] [PMID: 28683298]

[27]
He, J.; Xiong, X.; Yang, H.; Li, D.; Liu, X.; Li, S.; Liao, S.; Chen, S.; Wen, X.; Yu, K.; Fu, L.; Dong, X.; Zhu, K.; Xia, X.; Kang, T.; Bian, C.; Li, X.; Liu, H.; Ding, P.; Zhang, X.; Liu, Z.; Li, W.; Zuo, Z.; Zhou, P. Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response. Cell Res.,  2022, 32(6), 530-542.
 [http://dx.doi.org/10.1038/s41422-022-00627-9] [PMID: 35165422]

[28]
Patente, T.A.; Pinho, M.P.; Oliveira, A.A.; Evangelista, G.C.M.; Bergami-Santos, P.C.; Barbuto, J.A.M. Human dendritic cells: Their heterogeneity and clinical application potential in cancer immunotherapy. Front. Immunol.,  2019, 9, 3176.
 [http://dx.doi.org/10.3389/fimmu.2018.03176] [PMID: 30719026]

[29]
Deng, H.; Zhao, Y.; Cai, X.; Chen, H.; Cheng, B.; Zhong, R.; Li, F.; Xiong, S.; Li, J.; Liu, J.; He, J.; Liang, W. PD-L1 expression and Tumor mutation burden as Pathological response biomarkers of Neoadjuvant immunotherapy for Early-stage Non-small cell lung cancer: A systematic review and meta-analysis. Crit. Rev. Oncol. Hematol.,  2022, 170, 103582.
 [http://dx.doi.org/10.1016/j.critrevonc.2022.103582] [PMID: 35031441]

[30]
Jiang, X.; Wang, J.; Deng, X.; Xiong, F.; Ge, J.; Xiang, B.; Wu, X.; Ma, J.; Zhou, M.; Li, X.; Li, Y.; Li, G.; Xiong, W.; Guo, C.; Zeng, Z. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol. Cancer,  2019, 18(1), 10.
 [http://dx.doi.org/10.1186/s12943-018-0928-4] [PMID: 30646912]

[31]
Ricciuti, B.; Wang, X.; Alessi, J.V.; Rizvi, H.; Mahadevan, N.R.; Li, Y.Y.; Polio, A.; Lindsay, J.; Umeton, R.; Sinha, R.; Vokes, N.I.; Recondo, G.; Lamberti, G.; Lawrence, M.; Vaz, V.R.; Leonardi, G.C.; Plodkowski, A.J.; Gupta, H.; Cherniack, A.D.; Tolstorukov, M.Y.; Sharma, B.; Felt, K.D.; Gainor, J.F.; Ravi, A.; Getz, G.; Schalper, K.A.; Henick, B.; Forde, P.; Anagnostou, V.; Jänne, P.A.; Van Allen, E.M.; Nishino, M.; Sholl, L.M.; Christiani, D.C.; Lin, X.; Rodig, S.J.; Hellmann, M.D.; Awad, M.M. Association of high tumor mutation burden in non–small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels. JAMA Oncol.,  2022, 8(8), 1160-1168.
 [http://dx.doi.org/10.1001/jamaoncol.2022.1981] [PMID: 35708671]

[32]
Takx-Köhlen, B.C.M.J. Immunomodulators. Pharm. Weekbl.,  1992, 14(4), 245-252.
 [http://dx.doi.org/10.1007/BF01962546] [PMID: 1437506]

[33]
Ghosh, R.; Bryant, D.L.; Farone, A.L. Panax quinquefolius (North American Ginseng) Polysaccharides as Immunomodulators: Current research status and future directions. Molecules,  2020, 25(24), 5854.
 [http://dx.doi.org/10.3390/molecules25245854] [PMID: 33322293]

[34]
McCuaig, S.; Barras, D.; Mann, E.H.; Friedrich, M.; Bullers, S.J.; Janney, A.; Garner, L.C.; Domingo, E.; Koelzer, V.H.; Delorenzi, M.; Tejpar, S.; Maughan, T.S.; West, N.R.; Powrie, F. The interleukin 22 pathway interacts with mutant KRAS to promote poor prognosis in colon cancer. Clin. Cancer Res.,  2020, 26(16), 4313-4325.
 [http://dx.doi.org/10.1158/1078-0432.CCR-19-1086] [PMID: 32430479]

[35]
Yan, C.; Richmond, A. Hiding in the dark: Pan-cancer characterization of expression and clinical relevance of CD40 to immune checkpoint blockade therapy. Mol. Cancer,  2021, 20(1), 146.
 [http://dx.doi.org/10.1186/s12943-021-01442-3] [PMID: 34758832]

[36]
Oflazoglu, E.; Grewal, I.S.; Gerber, H. Targeting CD30/CD30L in oncology and autoimmune and inflammatory diseases. Adv. Exp. Med. Biol.,  2009, 647, 174-185.
 [http://dx.doi.org/10.1007/978-0-387-89520-8_12] [PMID: 19760074]

[37]
Iwata, R.; Lee, J.H.; Hayashi, M.; Dianzani, U.; Ofune, K.; Maruyama, M.; Oe, S.; Ito, T.; Hashiba, T.; Yoshimura, K.; Nonaka, M.; Nakano, Y.; Norian, L.; Nakano, I.; Asai, A. ICOSLG-mediated regulatory T cell expansion and IL-10 production promote progression of glioblastoma. Neuro-oncol.,  2019, 22(3), noz204.
 [http://dx.doi.org/10.1093/neuonc/noz204] [PMID: 31634400]

[38]
Starzer, A.M.; Berghoff, A.S. New emerging targets in cancer immunotherapy: CD27 (TNFRSF7). ESMO Open,  2019, 4(Suppl. 3), e000629.
 [http://dx.doi.org/10.1136/esmoopen-2019-000629] [PMID: 32152062]

[39]
Weng, Y.S.; Tseng, H.Y.; Chen, Y.A.; Shen, P.C.; Al Haq, A.T.; Chen, L.M.; Tung, Y.C.; Hsu, H.L. MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer. Mol. Cancer,  2019, 18(1), 42.
 [http://dx.doi.org/10.1186/s12943-019-0988-0] [PMID: 30885232]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1386207326666230410103255	Print ISSN 1386-2073
Publisher Name Bentham Science Publisher	Online ISSN 1875-5402

Combinatorial Chemistry & High Throughput Screening

Identification of CLIC5 as a Prognostic Biomarker and Correlated Immunomodulator for Lung Adenocarcinoma

Abstract Play Pause

Graphical Abstract

Related Journals

Abstract