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Current Genomics

Editor-in-Chief

ISSN (Print): 1389-2029
ISSN (Online): 1875-5488

Research Article

Comprehensive Analysis of Alternative Polyadenylation Events Associated with the Tumor Immune Microenvironment in Colon Adenocarcinoma

Author(s): Fangning Pang, Peng Yang, Tongfei Wang, Xuzhao Li, Xiaoyong Wu, Rong Yue, Bin Bai* and Qingchuan Zhao*

Volume 24, Issue 1, 2023

Published on: 26 May, 2023

Page: [48 - 61] Pages: 14

DOI: 10.2174/1389202924666230503122134

Price: $65

Abstract

Objective: Colon adenocarcinoma (COAD) is one of the leading causes of cancer death worldwide. Alternative polyadenylation (APA) is relevant to the variability of the 3'-UTR of mRNA. However, the posttranscriptional dysregulation of APA in COAD is poorly understood.

Methods: We collected APA data from The Cancer Genome Atlas (TCGA) COAD (n =7692). APA events were evaluated using PDUI values, and the prognostically significant APA events were screened by LASSO Cox regression to construct a prognostic model. Then, prognostic model functions and possible regulatory genes of characteristic APA events were analyzed. Finally, the immune regulatory network based on APA regulatory genes was analyzed and established.

Results: A total of 95 APA events were found to influence the COAD outcomes. Among them, 39 genes were screened as characteristic prognostic APA events by LASSO Cox regression to construct a COAD prognostic signature. The analysis results suggested that a high signature score was associated with poor prognosis and was significantly correlated with a variety of immune cells, including NK and Th1, 2 and 17 cells. Further analysis showed that APA regulators mainly served roles in the prognosis of COAD. Based on the above results, we constructed an immunoregulatory network for APA regulatory genes-APA genes-immune cells.

Conclusion: Our study revealed that APA events in COAD may regulate tumor progression by influencing immune cells, which provides a new direction for exploring the influencing mechanism of the tumor immune microenvironment and is expected to provide a potential new target for COAD immunotherapy.

Keywords: Alternative polyadenylation, COAD, 3'-UTR, immunity, NK cells, T cells.

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[1]
El Kinany, K.; Mint, S.D.M.; Hatime, Z.; Boudouaya, H.A.; Huybrechts, I.; El Asri, A.; Benider, A.; Ahallat, M.; Afqir, S.; Mellas, N.; Khouchani, M.; El Rhazi, K. Consumption of modern and traditional Moroccan dairy products and colorectal cancer risk: A large case control study. Eur. J. Nutr., 2020, 59(3), 953-963.
[http://dx.doi.org/10.1007/s00394-019-01954-1] [PMID: 30929068]
[2]
Rawla, P.; Sunkara, T.; Barsouk, A. Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors. Prz. Gastroenterol., 2019, 14(2), 89-103.
[http://dx.doi.org/10.5114/pg.2018.81072] [PMID: 31616522]
[3]
Roslan, N.H.; Makpol, S.; Mohd Yusof, Y.A. A review on dietary intervention in obesity associated colon cancer. Asian Pac. J. Cancer Prev., 2019, 20(5), 1309-1319.
[http://dx.doi.org/10.31557/APJCP.2019.20.5.1309] [PMID: 31127882]
[4]
Sun, Y.; Li, L.; Yao, W.; Liu, X.; Yang, Y.; Ma, B.; Xue, D. Ush2a mutation is associated with tumor mutation burden and antitumor immunity in patients with colon adenocarcinoma. Front. Genet., 2021, 12, 762160.
[http://dx.doi.org/10.3389/fgene.2021.762160] [PMID: 34795697]
[5]
Bao, X.; Zhang, H.; Wu, W.; Cheng, S.; Dai, X.; Zhu, X.; Fu, Q.; Tong, Z.; Liu, L.; Zheng, Y.; Zhao, P.; Fang, W.; Liu, F. Analysis of the molecular nature associated with microsatellite status in colon cancer identifies clinical implications for immunotherapy. J. Immunother. Cancer, 2020, 8(2), e001437.
[http://dx.doi.org/10.1136/jitc-2020-001437] [PMID: 33028695]
[6]
Sandhu, J.; Lavingia, V.; Fakih, M. Systemic treatment for metastatic colorectal cancer in the era of precision medicine. J. Surg. Oncol., 2019, 119(5), 564-582.
[http://dx.doi.org/10.1002/jso.25421] [PMID: 30802315]
[7]
Derti, A.; Garrett-Engele, P.; MacIsaac, K.D.; Stevens, R.C.; Sriram, S.; Chen, R.; Rohl, C.A.; Johnson, J.M.; Babak, T. A quantitative atlas of polyadenylation in five mammals. Genome Res., 2012, 22(6), 1173-1183.
[http://dx.doi.org/10.1101/gr.132563.111] [PMID: 22454233]
[8]
Elkon, R.; Ugalde, A.P.; Agami, R. Alternative cleavage and polyadenylation: Extent, regulation and function. Nat. Rev. Genet., 2013, 14(7), 496-506.
[http://dx.doi.org/10.1038/nrg3482] [PMID: 23774734]
[9]
Lin, S.; Gregory, R.I. MicroRNA biogenesis pathways in cancer. Nat. Rev. Cancer, 2015, 15(6), 321-333.
[http://dx.doi.org/10.1038/nrc3932] [PMID: 25998712]
[10]
Masamha, C.P.; Wagner, E.J. The contribution of alternative polyadenylation to the cancer phenotype. Carcinogenesis, 2018, 39(1), 2-10.
[http://dx.doi.org/10.1093/carcin/bgx096] [PMID: 28968750]
[11]
Mayr, C.; Bartel, D.P. Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell, 2009, 138(4), 673-684.
[http://dx.doi.org/10.1016/j.cell.2009.06.016] [PMID: 19703394]
[12]
Hoffman, Y.; Bublik, D.R.; Ugalde, A.P.; Elkon, R.; Biniashvili, T.; Agami, R.; Oren, M.; Pilpel, Y. 3'utr shortening potentiates microrna-based repression of pro-differentiation genes in proliferating human cells. PLoS Genet., 2016, 12(2), e1005879.
[http://dx.doi.org/10.1371/journal.pgen.1005879] [PMID: 26908102]
[13]
Erson-Bensan, A.E. Alternative polyadenylation and RNA-binding proteins. J. Mol. Endocrinol., 2016, 57(2), F29-F34.
[http://dx.doi.org/10.1530/JME-16-0070] [PMID: 27208003]
[14]
Loya, A.; Pnueli, L.; Yosefzon, Y.; Wexler, Y.; Ziv-Ukelson, M.; Arava, Y. The 3′-UTR mediates the cellular localization of an mRNA encoding a short plasma membrane protein. RNA, 2008, 14(7), 1352-1365.
[http://dx.doi.org/10.1261/rna.867208] [PMID: 18492794]
[15]
Begik, O.; Oyken, M.; Cinkilli Alican, T.; Can, T.; Erson-Bensan, A.E. Alternative polyadenylation patterns for novel gene discovery and classification in cancer. Neoplasia, 2017, 19(7), 574-582.
[http://dx.doi.org/10.1016/j.neo.2017.04.008] [PMID: 28624626]
[16]
Xiang, Y.; Ye, Y.; Lou, Y.; Yang, Y.; Cai, C.; Zhang, Z.; Mills, T.; Chen, N.Y.; Kim, Y.; Muge Ozguc, F.; Diao, L.; Karmouty-Quintana, H.; Xia, Y.; Kellems, R.E.; Chen, Z.; Blackburn, M.R.; Yoo, S.H.; Shyu, A.B.; Mills, G.B.; Han, L. Comprehensive characterization of alternative polyadenylation in human cancer. J. Natl. Cancer Inst., 2018, 110(4), 379-389.
[http://dx.doi.org/10.1093/jnci/djx223] [PMID: 29106591]
[17]
Xia, Z.; Donehower, L.A.; Cooper, T.A.; Neilson, J.R.; Wheeler, D.A.; Wagner, E.J.; Li, W. Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types. Nat. Commun., 2014, 5(1), 5274.
[http://dx.doi.org/10.1038/ncomms6274] [PMID: 25409906]
[18]
Bisognin, A.; Pizzini, S.; Perilli, L.; Esposito, G.; Mocellin, S.; Nitti, D.; Zanovello, P.; Bortoluzzi, S.; Mandruzzato, S. An integrative framework identifies alternative splicing events in colorectal cancer development. Mol. Oncol., 2014, 8(1), 129-141.
[http://dx.doi.org/10.1016/j.molonc.2013.10.004] [PMID: 24189147]
[19]
Yang, X.; Wu, J.; Xu, W.; Tan, S.; Chen, C.; Wang, X.; Sun, J.; Kang, Y. Genome-wide profiling reveals cancer-related genes with switched alternative polyadenylation sites in colorectal cancer. OncoTargets Ther., 2018, 11, 5349-5357.
[http://dx.doi.org/10.2147/OTT.S164233] [PMID: 30214241]
[20]
Zhang, Y.; Xu, Y.; Wang, Y. Alternative polyadenylation associated with prognosis and therapy in colorectal cancer. Sci. Rep., 2022, 12(1), 7036.
[http://dx.doi.org/10.1038/s41598-022-11089-9] [PMID: 35487956]
[21]
Feng, X.; Li, L.; Wagner, E.J.; Li, W. TC3A: The cancer 3′ UTR atlas. Nucleic Acids Res., 2018, 46(D1), D1027-D1030.
[http://dx.doi.org/10.1093/nar/gkx892] [PMID: 30053266]
[22]
Ye, Y.; Dai, Q.; Qi, H. A novel defined pyroptosis-related gene signature for predicting the prognosis of ovarian cancer. Cell Death Discov., 2021, 7(1), 71.
[http://dx.doi.org/10.1038/s41420-021-00451-x] [PMID: 33828074]
[23]
Fabian, M.R.; Sonenberg, N.; Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem., 2010, 79(1), 351-379.
[http://dx.doi.org/10.1146/annurev-biochem-060308-103103] [PMID: 20533884]
[24]
Sun, M.; Ding, J.; Li, D.; Yang, G.; Cheng, Z.; Zhu, Q. NUDT21 regulates 3′-UTR length and microRNA-mediated gene silencing in hepatocellular carcinoma. Cancer Lett., 2017, 410, 158-168.
[http://dx.doi.org/10.1016/j.canlet.2017.09.026] [PMID: 28964783]
[25]
Patel, S.A.; Minn, A.J. Combination cancer therapy with immune checkpoint blockade: Mechanisms and strategies. Immunity, 2018, 48(3), 417-433.
[http://dx.doi.org/10.1016/j.immuni.2018.03.007] [PMID: 29562193]
[26]
Zhang, J.; Zhou, N.; Lin, A.; Luo, P.; Chen, X.; Deng, H.; Kang, S.; Guo, L.; Zhu, W.; Zhang, J. ZFHX3 mutation as a protective biomarker for immune checkpoint blockade in non-small cell lung cancer. Cancer Immunol. Immunother., 2021, 70(1), 137-151.
[http://dx.doi.org/10.1007/s00262-020-02668-8] [PMID: 32653938]
[27]
Hurtado, C.G.; Wan, F.; Housseau, F.; Sears, C.L. Roles for interleukin 17 and adaptive immunity in pathogenesis of colorectal cancer. Gastroenterology, 2018, 155(6), 1706-1715.
[http://dx.doi.org/10.1053/j.gastro.2018.08.056] [PMID: 30218667]
[28]
Tosolini, M.; Kirilovsky, A.; Mlecnik, B.; Fredriksen, T.; Mauger, S.; Bindea, G.; Berger, A.; Bruneval, P.; Fridman, W.H.; Pagès, F.; Galon, J. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, Th2, TREG, Th17) in patients with colorectal cancer. Cancer Res., 2011, 71(4), 1263-1271.
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2907] [PMID: 21303976]
[29]
Kryczek, I.; Banerjee, M.; Cheng, P.; Vatan, L.; Szeliga, W.; Wei, S.; Huang, E.; Finlayson, E.; Simeone, D.; Welling, T.H.; Chang, A.; Coukos, G.; Liu, R.; Zou, W. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood, 2009, 114(6), 1141-1149.
[http://dx.doi.org/10.1182/blood-2009-03-208249] [PMID: 19470694]
[30]
Mandal, A.; Viswanathan, C. Natural killer cells: In health and disease. Hematol. Oncol. Stem Cell Ther., 2015, 8(2), 47-55.
[http://dx.doi.org/10.1016/j.hemonc.2014.11.006] [PMID: 25571788]
[31]
Bald, T.; Krummel, M.F.; Smyth, M.J.; Barry, K.C. The NK cell–cancer cycle: Advances and new challenges in NK cell–based immunotherapies. Nat. Immunol., 2020, 21(8), 835-847.
[http://dx.doi.org/10.1038/s41590-020-0728-z] [PMID: 32690952]
[32]
Marchalot, A.; Mjösberg, J. Innate lymphoid cells in colorectal cancer. Scand. J. Immunol., 2022, 95(4), e13156.
[http://dx.doi.org/10.1111/sji.13156] [PMID: 35274359]
[33]
Blake, D.; Lynch, K.W. The three as: Alternative splicing, alternative polyadenylation and their impact on apoptosis in immune function. Immunol. Rev., 2021, 304(1), 30-50.
[http://dx.doi.org/10.1111/imr.13018] [PMID: 34368964]
[34]
Shi, Y.; Di Giammartino, D.C.; Taylor, D.; Sarkeshik, A.; Rice, W.J.; Yates, J.R., III; Frank, J.; Manley, J.L. Molecular architecture of the human pre-mRNA 3′ processing complex. Mol. Cell, 2009, 33(3), 365-376.
[http://dx.doi.org/10.1016/j.molcel.2008.12.028] [PMID: 19217410]
[35]
Goodman, A.; Patel, S.P.; Kurzrock, R. PD-1–PD-L1 immune-checkpoint blockade in B-cell lymphomas. Nat. Rev. Clin. Oncol., 2017, 14(4), 203-220.
[http://dx.doi.org/10.1038/nrclinonc.2016.168] [PMID: 27805626]
[36]
Fidelle, M.; Yonekura, S.; Picard, M.; Cogdill, A.; Hollebecque, A.; Roberti, M.P.; Zitvogel, L. Resolving the paradox of colon cancer through the integration of genetics, immunology, and the microbiota. Front. Immunol., 2020, 11, 600886.
[http://dx.doi.org/10.3389/fimmu.2020.600886] [PMID: 33381121]

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