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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

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

Research Article

Carbonic Anhydrase 4 Serves as A Novel Prognostic Biomarker and Therapeutic Target for Non-Small Cell Lung Cancer: A Study Based on TCGA Samples

Author(s): Bo Xu, Yang Lou, Xiaoyi Xu, Xianshuai Li, Xin Tian, Zhaonan Yu and Xianguo Chen*

Volume 26, Issue 14, 2023

Published on: 28 April, 2023

Page: [2527 - 2540] Pages: 14

DOI: 10.2174/1386207326666230321091943

Price: $65

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Abstract

Background: Carbonic anhydrase 4 (CA4) is a member of a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide and was found to have low expression in non-small cell lung cancer (NSCLC). However, the specific role of CA4 in NSCLC and the underlying mechanisms remain unknown.

Methods: The bioinformatic analysis on lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets downloaded from The Cancer Genome Atlas (TCGA) database was performed. We found that CA4 expression was lower in tumors than that in normal tissues, which were verified by Real-time PCR. Lower CA4 levels were significantly associated with higher T stages in LUAD and LUSC cohorts. Multivariate analysis showed that CA4 is an independent prognostic factor for NSCLC. Furthermore, the expression of CA4 also correlated with immune infiltration and drug sensitivity.

Results: Ectopic expression of CA4 decreased NSCLC cell proliferation in vitro by CCK-8 assay. CA4 caused G0/G1 cell cycle arrest by cell experiments. Mechanistic studies found that CA affects the cell cycle and inhibits cell proliferation by downregulating the expression of CDK2.

Conclusion: The present findings highlight the role of CA4 in NSCLC and identify CA4 as a potential novel diagnostic and prognostic biomarker for the treatment of NSCLC.

Graphical Abstract

[1]
Vivarelli, S.; Salemi, R.; Candido, S.; Falzone, L.; Santagati, M.; Stefani, S.; Torino, F.; Banna, G.L.; Tonini, G.; Libra, M. Gut microbiota and cancer: From pathogenesis to therapy. Cancers, 2019, 11(1), 38.
[http://dx.doi.org/10.3390/cancers11010038] [PMID: 30609850]
[2]
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]
[3]
Chapman, C.J.; Murray, A.; McElveen, J.E.; Sahin, U.; Luxemburger, U.; Türeci, O.; Wiewrodt, R.; Barnes, A.C.; Robertson, J.F. Autoantibodies in lung cancer: Possibilities for early detection and subsequent cure. Thorax, 2008, 63(3), 228-233.
[http://dx.doi.org/10.1136/thx.2007.083592] [PMID: 17932110]
[4]
Lindskog, S. Structure and mechanism of carbonic anhydrase. Pharmacol. Ther., 1997, 74(1), 1-20.
[http://dx.doi.org/10.1016/S0163-7258(96)00198-2] [PMID: 9336012]
[5]
Mboge, M.; Mahon, B.; McKenna, R.; Frost, S. Carbonic anhydrases: Role in pH control and cancer. Metabolites, 2018, 8(1), 19.
[http://dx.doi.org/10.3390/metabo8010019] [PMID: 29495652]
[6]
Wang, B.; Jiang, H.; Wan, X.; Wang, Y.; Zheng, X.; Li, P.; Guo, J.; Ding, X.; Song, H. Carbonic anhydrase IV inhibits cell proliferation in gastric cancer by regulating the cell cycle. Oncol. Lett., 2020, 20(4), 4.
[http://dx.doi.org/10.3892/ol.2020.11865] [PMID: 32774478]
[7]
Zhang, J.; Tsoi, H.; Li, X.; Wang, H.; Gao, J.; Wang, K.; Go, M.Y.Y.; Ng, S.C.; Chan, F.K.L.; Sung, J.J.Y.; Yu, J. Carbonic anhydrase IV inhibits colon cancer development by inhibiting the Wnt signalling pathway through targeting the WTAP–WT1–TBL1 axis. Gut, 2016, 65(9), 1482-1493.
[http://dx.doi.org/10.1136/gutjnl-2014-308614] [PMID: 26071132]
[8]
Chen, J.; Hu, L.; Zhang, F.; Wang, J.; Chen, J.; Wang, Y. Downregulation of carbonic anhydrase IV contributes to promotion of cell proliferation and is associated with poor prognosis in non-small cell lung cancer. Oncol. Lett., 2017, 14(4), 5046-5050.
[http://dx.doi.org/10.3892/ol.2017.6740] [PMID: 29085519]
[9]
Weinstein, J.N.; Collisson, E.A.; Mills, G.B.; Shaw, K.R.M.; Ozenberger, B.A.; Ellrott, K.; Shmulevich, I.; Sander, C.; Stuart, J.M. The cancer genome atlas pan-cancer analysis project. Nat. Genet., 2013, 45(10), 1113-1120.
[http://dx.doi.org/10.1038/ng.2764] [PMID: 24071849]
[10]
Li, C.; Tang, Z.; Zhang, W.; Ye, Z.; Liu, F. GEPIA2021: Integrating multiple deconvolution-based analysis into GEPIA. Nucleic Acids Res., 2021, 49(W1), W242-W246.
[http://dx.doi.org/10.1093/nar/gkab418] [PMID: 34050758]
[11]
Li, J.H.; Liu, S.; Zhou, H.; Qu, L.H.; Yang, J.H. starBase v2.0: Decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res., 2014, 42(D1), D92-D97.
[http://dx.doi.org/10.1093/nar/gkt1248] [PMID: 24297251]
[12]
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]
[13]
Gao, J.; Aksoy, B.A.; Dogrusoz, U.; Dresdner, G.; Gross, B.; Sumer, S.O.; Sun, Y.; Jacobsen, A.; Sinha, R.; Larsson, E.; Cerami, E.; Sander, C.; Schultz, N. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal., 2013, 6(269), pl1.
[http://dx.doi.org/10.1126/scisignal.2004088] [PMID: 23550210]
[14]
Geeleher, P.; Cox, N.; Huang, R.S. pRRophetic: An R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS One, 2014, 9(9), e107468.
[http://dx.doi.org/10.1371/journal.pone.0107468] [PMID: 25229481]
[15]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[16]
Molina, J.R.; Yang, P.; Cassivi, S.D.; Schild, S.E.; Adjei, A.A. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin. Proc., 2008, 83(5), 584-594.
[http://dx.doi.org/10.1016/S0025-6196(11)60735-0] [PMID: 18452692]
[17]
Chen, G.; Luo, D.; Zhong, N.; Li, D.; Zheng, J.; Liao, H.; Li, Z.; Lin, X.; Chen, Q.; Zhang, C.; Lu, Y.; Chan, Y.T.; Ren, Q.; Wang, N.; Feng, Y. GPC2 is a potential diagnostic, immunological, and prognostic biomarker in pan-cancer. Front. Immunol., 2022, 13, 857308.
[http://dx.doi.org/10.3389/fimmu.2022.857308] [PMID: 35345673]
[18]
Sun, J.; Xie, T.; Jamal, M.; Tu, Z.; Li, X.; Wu, Y.; Li, J.; Zhang, Q.; Huang, X. CLEC3B as a potential diagnostic and prognostic biomarker in lung cancer and association with the immune microenvironment. Cancer Cell Int., 2020, 20(1), 106.
[http://dx.doi.org/10.1186/s12935-020-01183-1] [PMID: 32265595]
[19]
Bai, Y.; Liu, X.; Qi, X.; Liu, X.; Peng, F.; Li, H.; Fu, H.; Pei, S.; Chen, L.; Chi, X.; Zhang, L.; Zhu, X.; Song, Y.; Wang, Y.; Meng, S.; Jiang, T.; Shao, S. PDIA6 modulates apoptosis and autophagy of non-small cell lung cancer cells via the MAP4K1/JNK signaling pathway. EBio. Medic., 2019, 42, 311-325.
[http://dx.doi.org/10.1016/j.ebiom.2019.03.045] [PMID: 30922965]
[20]
Supuran, C.T. Structure and function of carbonic anhydrases. Biochem. J., 2016, 473(14), 2023-2032.
[http://dx.doi.org/10.1042/BCJ20160115] [PMID: 27407171]
[21]
Supuran, C.T. Carbonic anhydrases: Novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov., 2008, 7(2), 168-181.
[http://dx.doi.org/10.1038/nrd2467] [PMID: 18167490]
[22]
Xu, Y.; Xu, W.H.; Shi, S.N.; Yang, X.L.; Ren, Y.R.; Zhuang, X.Y.; Qu, Y.Y.; Zhang, H.L.; Zhang, X.F. Carbonic anhydrase 4 serves as a clinicopathological biomarker for outcomes and immune infiltration in renal cell carcinoma, lower grade glioma, lung adenocarcinoma and uveal melanoma. J. Cancer, 2020, 11(20), 6101-6113.
[http://dx.doi.org/10.7150/jca.46902] [PMID: 32922550]
[23]
Guglietta, S.; Rescigno, M. Hypercoagulation and complement: Connected players in tumor development and metastases. Semin. Immunol., 2016, 28(6), 578-586.
[http://dx.doi.org/10.1016/j.smim.2016.10.011] [PMID: 27876232]
[24]
Shao, B.Z.; Yao, Y.; Li, J.P.; Chai, N.L.; Linghu, E.Q. The role of neutrophil extracellular traps in cancer. Front. Oncol., 2021, 11, 714357.
[http://dx.doi.org/10.3389/fonc.2021.714357] [PMID: 34476216]
[25]
Dou, Z.; Ghosh, K.; Vizioli, M.G.; Zhu, J.; Sen, P.; Wangensteen, K.J.; Simithy, J.; Lan, Y.; Lin, Y.; Zhou, Z.; Capell, B.C.; Xu, C.; Xu, M.; Kieckhaefer, J.E.; Jiang, T.; Shoshkes-Carmel, M.; Tanim, K.M.A.A.; Barber, G.N.; Seykora, J.T.; Millar, S.E.; Kaestner, K.H.; Garcia, B.A.; Adams, P.D.; Berger, S.L. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature, 2017, 550(7676), 402-406.
[http://dx.doi.org/10.1038/nature24050] [PMID: 28976970]
[26]
Harlin, H.; Meng, Y.; Peterson, A.C.; Zha, Y.; Tretiakova, M.; Slingluff, C.; McKee, M.; Gajewski, T.F. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res., 2009, 69(7), 3077-3085.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-2281] [PMID: 19293190]
[27]
Marcus, A.; Mao, A.J.; Lensink-Vasan, M.; Wang, L.; Vance, R.E.; Raulet, D.H. Tumor-Derived cGAMP Triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity, 2018, 49(4), 754-763.e4.
[http://dx.doi.org/10.1016/j.immuni.2018.09.016] [PMID: 30332631]
[28]
Jiang, M.; Chen, P.; Wang, L.; Li, W.; Chen, B.; Liu, Y.; Wang, H.; Zhao, S.; Ye, L.; He, Y.; Zhou, C. cGAS-STING, an important pathway in cancer immunotherapy. J. Hematol. Oncol., 2020, 13(1), 81.
[http://dx.doi.org/10.1186/s13045-020-00916-z] [PMID: 32571374]
[29]
Tian, Z.; Zeng, Y.; Peng, Y.; Liu, J.; Wu, F. Cancer immunotherapy strategies that target the cGAS-STING pathway. Front. Immunol., 2022, 13, 996663.
[http://dx.doi.org/10.3389/fimmu.2022.996663] [PMID: 36353640]
[30]
Bremnes, R.M.; Busund, L.T.; Kilvær, T.L.; Andersen, S.; Richardsen, E.; Paulsen, E.E.; Hald, S.; Khanehkenari, M.R.; Cooper, W.A.; Kao, S.C.; Dønnem, T. The role of tumor-infiltrating lymphocytes in development, progression, and prognosis of non–small cell lung cancer. J. Thorac. Oncol., 2016, 11(6), 789-800.
[http://dx.doi.org/10.1016/j.jtho.2016.01.015] [PMID: 26845192]
[31]
Cohen, M.; Giladi, A.; Barboy, O.; Hamon, P.; Li, B.; Zada, M.; Gurevich-Shapiro, A.; Beccaria, C.G.; David, E.; Maier, B.B.; Buckup, M.; Kamer, I.; Deczkowska, A.; Le Berichel, J.; Bar, J.; Iannacone, M.; Tanay, A.; Merad, M.; Amit, I. The interaction of CD4+ helper T cells with dendritic cells shapes the tumor microenvironment and immune checkpoint blockade response. Nat. Can., 2022, 3(3), 303-317.
[http://dx.doi.org/10.1038/s43018-022-00338-5] [PMID: 35241835]
[32]
Banta, K.L.; Xu, X.; Chitre, A.S.; Au-Yeung, A.; Takahashi, C.; O’Gorman, W.E.; Wu, T.D.; Mittman, S.; Cubas, R.; Comps-Agrar, L.; Fulzele, A.; Bennett, E.J.; Grogan, J.L.; Hui, E.; Chiang, E.Y.; Mellman, I. Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses. Immunity, 2022, 55(3), 512-526.e9.
[http://dx.doi.org/10.1016/j.immuni.2022.02.005] [PMID: 35263569]
[33]
Redin, E.; Garmendia, I.; Lozano, T.; Serrano, D.; Senent, Y.; Redrado, M.; Villalba, M.; De Andrea, C.E.; Exposito, F.; Ajona, D.; Ortiz-Espinosa, S.; Remirez, A.; Bertolo, C.; Sainz, C.; Garcia-Pedrero, J.; Pio, R.; Lasarte, J.; Agorreta, J.; Montuenga, L.M.; Calvo, A. SRC family kinase (SFK) inhibitor dasatinib improves the antitumor activity of anti-PD-1 in NSCLC models by inhibiting Treg cell conversion and proliferation. J. Immunother. Cancer, 2021, 9(3), e001496.
[http://dx.doi.org/10.1136/jitc-2020-001496] [PMID: 33658304]
[34]
Gaudreau, P.O.; Negrao, M.V.; Mitchell, K.G.; Reuben, A.; Corsini, E.M.; Li, J.; Karpinets, T.V.; Wang, Q.; Diao, L.; Wang, J.; Federico, L.; Parra-Cuentas, E.R.; Khairullah, R.; Behrens, C.; Correa, A.M.; Gomez, D.; Little, L.; Gumbs, C.; Kadara, H.N.; Fujimoto, J.; McGrail, D.J.; Vaporciyan, A.A.; Swisher, S.G.; Walsh, G.; Antonoff, M.B.; Weissferdt, A.; Tran, H.; Roarty, E.; Haymaker, C.; Bernatchez, C.; Zhang, J.; Futreal, P.A.; Wistuba, I.I.; Cascone, T.; Heymach, J.V.; Sepesi, B.; Zhang, J.; Gibbons, D.L. Neoadjuvant chemotherapy increases cytotoxic t cell, tissue resident memory T Cell, and B cell infiltration in resectable NSCLC. J. Thorac. Oncol., 2021, 16(1), 127-139.
[http://dx.doi.org/10.1016/j.jtho.2020.09.027] [PMID: 33096269]
[35]
Tøndell, A.; Subbannayya, Y.; Wahl, S.G.F.; Flatberg, A.; Sørhaug, S.; Børset, M.; Haug, M. Analysis of intra-tumoral macrophages and t cells in non-small cell lung cancer (nsclc) indicates a role for immune checkpoint and CD200-CD200R interactions. Cancers, 2021, 13(8), 1788.
[http://dx.doi.org/10.3390/cancers13081788] [PMID: 33918618]
[36]
Pockley, A.G.; Vaupel, P.; Multhoff, G. NK cell-based therapeutics for lung cancer. Expert Opin. Biol. Ther., 2020, 20(1), 23-33.
[http://dx.doi.org/10.1080/14712598.2020.1688298] [PMID: 31714156]
[37]
Principe, D.R.; Chiec, L.; Mohindra, N.A.; Munshi, H.G. Regulatory T-Cells as an Emerging Barrier to Immune Checkpoint Inhibition in Lung Cancer. Front. Oncol., 2021, 11, 684098.
[http://dx.doi.org/10.3389/fonc.2021.684098] [PMID: 34141625]
[38]
Deng, J.; Wang, J.; Khan, M.; Yu, P.; Yang, F.; Liang, H. Structure and biological properties of five Pt(II) complexes as potential anticancer agents. J. Inorg. Biochem., 2018, 185, 10-16.
[http://dx.doi.org/10.1016/j.jinorgbio.2018.04.017] [PMID: 29730232]

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