Comprehensive Analysis of Alternative Polyadenylation and Related Factors in Breast Cancer

doi:10.3870/j.issn.1672-0741.25.01.013

Abstract

Abstract: Objective By integrating multi-omics and clinical information,we conducted a comprehensive analysis of specific alternative polyadenylation(APA)alterations and their prognostic significance in breast cancer(BRCA)and explored the key upstream and downstream regulatory factors involved. Methods Multiple omics datasets from the TCGA and GTEx cohorts were integrated to identify dysregulated APA events in BRCA.Clinical information and LASSO Cox regression analysis were used to identify APA events associated with prognosis.Potential upstream APA regulators and somatic mutations influencing prognostic APA events were identified through multivariate linear regression and LASSO regression analyses.Finally,changes in downstream miRNA binding sites associated with APA events were analyzed based on miRNA-3′untranslated regions(3′UTR) regulatory information. Results An in-depth and systematic analysis of APA profiles in BRCA revealed widespread APA dysregulation,with 77.37% of altered APA events involving transcript shortening,predominantly affecting cancer- and immune-related processes.A total of 112 prognosis-related APA events were identified,and an overall survival(OS)prediction signature was constructed on the basis of 10 core APA events.Further analysis pinpointed SNRNP70 and PABPN1 as crucial regulators of APA deregulation,with SNRNP70 downregulation potentially causing APA-mediated shortening of STARD10.Moreover,systematic analysis of APA-modulated somatic mutations revealed that they were associated with 82.44% of dysregulated APA events and may influence APA by altering gene function.The construction of an APA-miRNA network for BRCA further revealed that APA-oriented dysfunction in STARD10 arises from its evasion of miR-325-3p suppression. Conclusion This study identified a series of prognosis-related APA events and their critical upstream and downstream regulatory factors through an integrative multi-omics approach,providing insights into the regulatory mechanisms of APA in BRCA.

Key words: alternative polyadenylation, breast cancer, prognostic analysis, miRNA regulatory network, oncogenes

CLC Number:

R737.9

Huang Liyun, Qin Liuyu, Jiang Yun et al. Comprehensive Analysis of Alternative Polyadenylation and Related Factors in Breast Cancer[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(1): 34-44.

References

[1] Sung H,Ferlay J,Siegel R L,et al.Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2021,71(3):209-249.
[2] Ferlay J,Colombet M,Soerjomataram I,et al.Estimating the global cancer incidence and mortality in 2018:GLOBOCAN sources and methods[J].Int J Cancer,2019,144(8):1941-1953.
[3] Qu C,Zhao Y,Feng G,et al.RPA3 is a potential marker of prognosis and radioresistance for nasopharyngeal carcinoma[J].J Cell Mol Med,2017,21(11):2872-2883.
[4] Zheng D and Tian B.RNA-binding proteins in regulation of alternative cleavage and polyadenylation[J].Adv Exp Med Biol,2014,825:97-127.
[5] Leung M K K,Delong A,Frey B J.Inference of the human polyadenylation code[J].Bioinformatics,2018,34(17):2889-2898.
[6] Sandberg R,Neilson J R,Sarma A,et al.Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites[J].Science,2008,320(5883):1643-1647.
[7] Mayr C and Bartel D P.Widespread shortening of 3′UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells[J].Cell,2009,138(4):673-684.
[8] Erson-Bensan A E.Alternative polyadenylation and RNA-binding proteins[J].J Mol Endocrinol,2016,57(2):F29-F34.
[9] Rosenwald A,Wright G,Wiestner A,et al.The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma[J].Cancer Cell,2003,3(2):185-197.
[10] Chu Y,Elrod N,Wang C,et al.Nudt21 regulates the alternative polyadenylation of Pak1 and is predictive in the prognosis of glioblastoma patients[J].Oncogene,2019,38(21):4154-4168.
[11] Tan S,Li H,Zhang W,et al.NUDT21 negatively regulates PSMB2 and CXXC5 by alternative polyadenylation and contributes to hepatocellular carcinoma suppression[J].Oncogene,2018,37(35):4887-4900.
[12] Masamha C P,Xia Z,Yang J,et al.CFIm25 links alternative polyadenylation to glioblastoma tumour suppression[J].Nature,2014,510(7505):412-416.
[13] Masamha C P and Wagner E J.The contribution of alternative polyadenylation to the cancer phenotype[J].Carcinogenesis,2018,39(1):2-10.
[14] Xiang Y,Ye Y,Lou Y,et al.Comprehensive characterization of alternative polyadenylation in human cancer[J].J Natl Cancer Inst,2018,110(4):379-389.
[15] Jiao X,Katiyar S,Willmarth N E,et al.C-JUN induces mammary epithelial cellular invasion and breast cancer stem cell expansion[J].J Biol Chem,2010,285(11):8218-8226.
[16] Tomczak K,Czerwińska P,Wiznerowicz M.The cancer geno-me atlas(TCGA):An immeasurable source of knowledge[J].Contemp Oncol(Pozn),2015,19(1a):A68-77.
[17] GTEx Consortium.The genotype-tissue expression(GTEx)project[J].Nat Genet,2013,45(6):580-585.
[18] Hong W,Ruan H,Zhang Z,et al.Apaatlas:Decoding alternative polyadenylation across human tissues[J].Nucleic Acids Res,2020,48(D1):D34-D39.
[19] Feng X,Li L,Wagner E J,et al.TC3A:The cancer 3′ UTR atlas[J].Nucleic Acids Res,2018,46(D1):D1027-D1030.
[20] Ogorodnikov A,Levin M,Tattikota S,et al.Transcriptome 3′end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma[J].Nat Commun,2018,9(1):5331.
[21] Agarwal V,Bell G W,Nam J W,et al.Predicting effective microRNA target sites in mammalian mrnas[J].Elife,2015,4:e05005.
[22] McGeary S E,Lin K S,Shi C Y,et al.The biochemical basis of microrna targeting efficacy[J].Science,2019,366(6472):eaav1741.
[23] Arianfar E,Shahgordi S,Memarian A.Natural killer cell defects in breast cancer:A key pathway for tumor evasion[J].Int Rev Immunol,2021,40(3):197-216.
[24] Souza-Fonseca-Guimaraes F,Cursons J,Huntington N D.The emergence of natural killer cells as a major target in cancer immunotherapy[J].Trends Immunol,2019,40(2):142-158.
[25] Ahmed Mohmmed E,Shousha W G,El-Saiid A S,et al.A cl-inical evaluation of circulating MiR-106 a and Raf-1 as breast cancer diagnostic and prognostic markers[J].Asian Pac J Cancer Prev,2021,22(11):3513-3520.
[26] de Kruijf E M,Sajet A,van Nes J G,et al.Hla-e and hla-g expression in classical hla class i-negative tumors is of prognostic value for clinical outcome of early breast cancer patients[J].J Immunol,2010,185(12):7452-7459.
[27] Su P,Ahmad B,Zou K,et al.Β-elemene enhances the chemotherapeutic effect of 5-fluorouracil in triple-negative breast cancer via PI3K/AKT,RAF-MEK-ErK,and NF-kappaB signaling pathways[J].Onco Targets Ther,2020,13:5207-5222.
[28] Giltnane J M and Balko J M.Rationale for targeting the Ras/MAPK pathway in triple-negative breast cancer[J].Discov Med,2014,17(95):275-283.
[29] O′Shea J,Cremona M,Morgan C,et al.A preclinical evaluation of the mek inhibitor refametinib in HER2-positive breast cancer cell lines including those with acquired resistance to trastuzumab or lapatinib[J].Oncotarget,2017,8(49):85120-85135.
[30] Zhou M,Long W,Xiong M,et al.Comprehensive analysis of alternative polyadenylation regulators of CTLA4 and immune infiltration in clear cell renal cell carcinoma[J].Transl Androl Urol,2023,12(4):533-548.
[31] Murphy N C,Biankin A V,Millar E K,et al.Loss of STARD10 expression identifies a group of poor prognosis breast cancers independent of HER2/Neu and triple negative status[J].Int J Cancer,2010,126(6):1445-1453.
[32] Cordover E,Wei J,Patel C,et al.KPT-9274,an inhibitor of PAK4 and NAMPT,leads to downregulation of mTORC2 in triple negative breast cancer cells[J].Chem Res Toxicol,2020,33(2):482-491.
[33] Zhao C,Ling X,Li X,et al.MicroRNA-138-5p inhibits cell m-igration,invasion and EMT in breast cancer by directly targeting RHBDD1[J].Breast Cancer,2019,26(6):817-825.
[34] Jin Y,Zhao M,Xie Q,et al.MicroRNA-338-3p functions as tumor suppressor in breast cancer by targeting SOX4[J].Int J Oncol,2015,47(4):1594-1602.
[35] Wang H,Hu X,Yang F,et al.miR-325-3p promotes the proliferation,invasion,and EMT of breast cancer cells by directly targeting S100 A2[J].Oncol Res,2021,28(7):731-744.
[36] Thomas L F and Sætrom P.Single nucleotide polymorphisms can create alternative polyadenylation signals and affect gene expression through loss of microRNA-regulation[J].PLoS Comput Biol,2012,8(8):e1002621.
[37] Lin A,Ji P,Niu X,et al.CstF64-induced shortening of the BID 3′UTR promotes esophageal squamous cell carcinoma progression by disrupting ceRNA cross-talk with ZFP36 L2[J].Cancer Res,2021,81(22):5638-5651.
[38] Venkat S,Tisdale A A,Schwarz J R,et al.Alternative polyadenylation drives oncogenic gene expression in pancreatic ductal adenocarcinoma[J].Genome Res,2020,30(3):347-360.
[39] Gruber A J,Zavolan M.Alternative cleavage and polyadenylation in health and disease[J].Nat Rev Genet,2019,20(10):599-614.
[40] Hashemi M,Yousefi J,Hashemi S M,et al.Association bet-ween programmed cell death 6 interacting protein insertion/deletion polymorphism and the risk of breast cancer in a sample of iranian population[J].Dis Markers,2015,2015:854621.