Prognostic value and potential function of splicing events in prostate adenocarcinoma

Huang,Zhi-Guang; He,Rong-Quan; Mo,Zeng-Nan

doi:10.3892/ijo.2018.4563

Prognostic value and potential function of splicing events in prostate adenocarcinoma

Authors:
- Zhi-Guang Huang
- Rong-Quan He
- Zeng-Nan Mo
View Affiliations

Affiliations: Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China, Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: September 17, 2018 https://doi.org/10.3892/ijo.2018.4563
Pages: 2473-2487
Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Prostate adenocarcinoma (PRAD) is one of the most common types of malignancy in males and at present, effective prognostic indicators are limited. The development of PRAD has been associated with abnormalities in alternative splicing (AS), a requisite biological process of gene expression in eukaryotic cells; however, the prognostic value of AS products and splicing events remains to be elucidated. In the present study, the data of splicing events and the clinical information of PRAD patients were obtained from The Cancer Genome Atlas (TCGA)SpliceSeq and TCGA databases, respectively. A prognostic index (PI) was generated from disease-free survival-associated splicing events (DFS-SEs), which were identified by univariate/multivariate Cox regression analysis. A total of 6,909 DFS-SEs were identified in PRAD. The corresponding genes for the DFS-SEs were significantly enriched in mitochondria and their associated pathways according to Gene Ontology annotation and in the pathways of fatty acid metabolism, oxidative phosphorylation and Huntington's disease according to a Kyoto Encyclopedia of Genes and Genomes pathway analysis. The PI for mutually exclusive exons had the greatest ability to predict the probability of five-year disease-free survival of patients with PRAD, with an area under the time-dependent receiver-operating characteristic curve of 0.7606. Patients with PRAD, when divided into a ‘low’ and a ‘high’ group based on their median PI for exon skip values, exhibited a marked difference in disease-free survival (low vs. high, 3,588.45±250.51 vs. 1,531.08±136.50 days; P=7.43x10-9). A correlation network between DFS-SEs of splicing factors and non-splicing factors was constructed to determine the potential mechanisms in PRAD, which included the potential regulatory interaction between the splicing event of splicing factor RNA binding motif protein 5-alternate terminator (AT)-64957 and the splicing event of non-splicing factor heterochromatin protein 1 binding protein 3-AT-939. In conclusion, the PIs derived from DFS-SEs are valuable prognostic factors for patients with PRAD, and the function of splicing events in PRAD deserves further exploration.

View Figures

View References

1	Salinas CA, Tsodikov A, Ishak-Howard M and Cooney KA: Prostate cancer in young men: An important clinical entity. Nat Rev Urol. 11:317–323. 2014. View Article : Google Scholar : PubMed/NCBI
2	Tabayoyong W and Abouassaly R: Prostate Cancer Screening and the Associated Controversy. Surg Clin North Am. 95:1023–1039. 2015. View Article : Google Scholar : PubMed/NCBI
3	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
4	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
5	Etzioni R, Tsodikov A, Mariotto A, Szabo A, Falcon S, Wegelin J, DiTommaso D, Karnofski K, Gulati R, Penson DF, et al: Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control. 19:175–181. 2008. View Article : Google Scholar
6	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
7	Kontos CK, Adamopoulos PG and Scorilas A: Prognostic and predictive biomarkers in prostate cancer. Expert Rev Mol Diagn. 15:1567–1576. 2015. View Article : Google Scholar : PubMed/NCBI
8	Dimakakos A, Armakolas A and Koutsilieris M: Novel tools for prostate cancer prognosis, diagnosis, and follow-up. BioMed Res Int. 2014:8906972014. View Article : Google Scholar : PubMed/NCBI
9	Thalgott M, Rack B, Maurer T, Souvatzoglou M, Eiber M, Kress V, Heck MM, Andergassen U, Nawroth R, Gschwend JE, et al: Detection of circulating tumor cells in different stages of prostate cancer. J Cancer Res Clin Oncol. 139:755–763. 2013. View Article : Google Scholar : PubMed/NCBI
10	Hessels D and Schalken JA: Urinary biomarkers for prostate cancer: A review. Asian J Androl. 15:333–339. 2013. View Article : Google Scholar : PubMed/NCBI
11	Wagner SD and Berglund JA: Alternative pre-mRNA splicing. Methods Mol Biol. 1126:45–54. 2014. View Article : Google Scholar : PubMed/NCBI
12	Kelemen O, Convertini P, Zhang Z, Wen Y, Shen M, Falaleeva M and Stamm S: Function of alternative splicing. Gene. 514:1–30. 2013. View Article : Google Scholar
13	Krause WC, Shafi AA, Nakka M and Weigel NL: Androgen receptor and its splice variant, AR-V7, differentially regulate FOXA1 sensitive genes in LNCaP prostate cancer cells. Int J Biochem Cell Biol. 54:49–59. 2014. View Article : Google Scholar : PubMed/NCBI
14	Lapuk AV, Volik SV, Wang Y and Collins CC: The role of mRNA splicing in prostate cancer. Asian J Androl. 16:515–521. 2014. View Article : Google Scholar : PubMed/NCBI
15	Liu LL, Xie N, Sun S, Plymate S, Mostaghel E and Dong X: Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene. 33:3140–3150. 2014. View Article : Google Scholar
16	Sprenger CC and Plymate SR: The link between androgen receptor splice variants and castration-resistant prostate cancer. Horm Cancer. 5:207–217. 2014. View Article : Google Scholar : PubMed/NCBI
17	Omenn GS, Menon R and Zhang Y: Innovations in proteomic profiling of cancers: Alternative splice variants as a new class of cancer biomarker candidates and bridging of proteomics with structural biology. J Proteomics. 90:28–37. 2013. View Article : Google Scholar : PubMed/NCBI
18	Li Y, Sun N, Lu Z, Sun S, Huang J, Chen Z and He J: Prognostic alternative mRNA splicing signature in non-small cell lung cancer. Cancer Lett. 393:40–51. 2017. View Article : Google Scholar : PubMed/NCBI
19	Ryan MC, Cleland J, Kim R, Wong WC and Weinstein JN: SpliceSeq: A resource for analysis and visualization of RNA-Seq data on alternative splicing and its functional impacts. Bioinformatics. 28:2385–2387. 2012. View Article : Google Scholar : PubMed/NCBI
20	Sveen A, Kilpinen S, Ruusulehto A, Lothe RA and Skotheim RI: Aberrant RNA splicing in cancer; expression changes and driver mutations of splicing factor genes. Oncogene. 35:2413–2427. 2016. View Article : Google Scholar
21	Yoshida K and Ogawa S: Splicing factor mutations and cancer. Wiley Interdiscip Rev RNA. 5:445–459. 2014. View Article : Google Scholar : PubMed/NCBI
22	Ogawa S: Splicing factor mutations in myelodysplasia. Int J Hematol. 96:438–442. 2012. View Article : Google Scholar : PubMed/NCBI
23	Silipo M, Gautrey H and Tyson-Capper A: Deregulation of splicing factors and breast cancer development. J Mol Cell Biol. 7:388–401. 2015. View Article : Google Scholar : PubMed/NCBI
24	Karni R, de Stanchina E, Lowe SW, Sinha R, Mu D and Krainer AR: The gene encoding the splicing factor SF2/ASF is a proto-oncogene. Nat Struct Mol Biol. 14:185–193. 2007. View Article : Google Scholar : PubMed/NCBI
25	Adler AS, McCleland ML, Yee S, Yaylaoglu M, Hussain S, Cosino E, Quinones G, Modrusan Z, Seshagiri S, Torres E, et al: An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth. Genes Dev. 28:1068–1084. 2014. View Article : Google Scholar : PubMed/NCBI
26	Ryan M, Wong WC, Brown R, Akbani R, Su X, Broom B, Melott J and Weinstein J: TCGASpliceSeq a compendium of alternative mRNA splicing in cancer. Nucleic Acids Res. 44:D1018–D1022. 2016. View Article : Google Scholar :
27	Heagerty PJ, Lumley T and Pepe MS: Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 56:337–344. 2000. View Article : Google Scholar : PubMed/NCBI
28	Piva F, Giulietti M, Burini AB and Principato G: SpliceAid 2: A database of human splicing factors expression data and RNA target motifs. Hum Mutat. 33:81–85. 2012. View Article : Google Scholar
29	Lex A, Gehlenborg N, Strobelt H, Vuillemot R and Pfister H: UpSet: Visualization of intersecting sets. IEEE Trans Vis Comput Graph. 20:1983–1992. 2014. View Article : Google Scholar
30	Fredericks AM, Cygan KJ, Brown BA and Fairbrother WG: RNA-Binding Proteins: Splicing Factors and Disease. Biomolecules. 5:893–909. 2015. View Article : Google Scholar : PubMed/NCBI
31	He Y, Lu J, Ye Z, Hao S, Wang L, Kohli M, Tindall DJ, Lim B, Zhu R, Wang L, et al: Androgen receptor splice variants bind to constitutively open chromatin and promote abiraterone-resistant growth of prostate cancer. Nucleic Acids Res. 46:1895–1911. 2018. View Article : Google Scholar : PubMed/NCBI
32	Munkley J, Livermore K, Rajan P and Elliott DJ: RNA splicing and splicing regulator changes in prostate cancer pathology. Hum Genet. 136:1143–1154. 2017. View Article : Google Scholar : PubMed/NCBI
33	Ciccarese C, Santoni M, Brunelli M, Buti S, Modena A, Nabissi M, Artibani W, Martignoni G, Montironi R, Tortora G, et al: AR-V7 and prostate cancer: The watershed for treatment selection? Cancer Treat Rev. 43:27–35. 2016. View Article : Google Scholar : PubMed/NCBI
34	Couture F, Sabbagh R, Kwiatkowska A, Desjardins R, Guay SP, Bouchard L and Day R: PACE4 Undergoes an Oncogenic Alternative Splicing Switch in Cancer. Cancer Res. 77:6863–6879. 2017. View Article : Google Scholar : PubMed/NCBI
35	Hernandez JR, Kim JJ, Verdone JE, Liu X, Torga G, Pienta KJ and Mooney SM: Alternative CD44 splicing identifies epithelial prostate cancer cells from the mesenchymal counterparts. Med Oncol. 32:1592015. View Article : Google Scholar : PubMed/NCBI
36	Cappellari M, Bielli P, Paronetto MP, Ciccosanti F, Fimia GM, Saarikettu J, Silvennoinen O and Sette C: The transcriptional co-activator SND1 is a novel regulator of alternative splicing in prostate cancer cells. Oncogene. 33:3794–3802. 2014. View Article : Google Scholar
37	Robert C and Watson M: The incredible complexity of RNA splicing. Genome Biol. 17:2652016. View Article : Google Scholar
38	Brasky TM, Darke AK, Song X, Tangen CM, Goodman PJ, Thompson IM, Meyskens FL Jr, Goodman GE, Minasian LM, Parnes HL, et al: Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst. 105:1132–1141. 2013. View Article : Google Scholar : PubMed/NCBI
39	Bassett JK, Severi G, Hodge AM, MacInnis RJ, Gibson RA, Hopper JL, English DR and Giles GG: Plasma phospholipid fatty acids, dietary fatty acids and prostate cancer risk. Int J Cancer. 133:1882–1891. 2013. View Article : Google Scholar : PubMed/NCBI
40	Moreel X, Allaire J, Léger C, Caron A, Labonté MÈ, Lamarche B, Julien P, Desmeules P, Têtu B and Fradet V: Prostatic and dietary omega-3 fatty acids and prostate cancer progression during active surveillance. Cancer Prev Res (Phila). 7:766–776. 2014. View Article : Google Scholar
41	Gang X, Yang Y, Zhong J, Jiang K, Pan Y, Karnes RJ, Zhang J, Xu W, Wang G and Huang H: P300 acetyltransferase regulates fatty acid synthase expression, lipid metabolism and prostate cancer growth. Oncotarget. 7:15135–15149. 2016. View Article : Google Scholar : PubMed/NCBI
42	Xiao D, Powolny AA, Moura MB, Kelley EE, Bommareddy A, Kim SH, Hahm ER, Normolle D, Van Houten B and Singh SV: Phenethyl isothiocyanate inhibits oxidative phosphorylation to trigger reactive oxygen species-mediated death of human prostate cancer cells. J Biol Chem. 285:26558–26569. 2010. View Article : Google Scholar : PubMed/NCBI
43	Chen ZP, Li M, Zhang LJ, He JY, Wu L, Xiao YY, Duan JA, Cai T and Li WD: Mitochondria-targeted drug delivery system for cancer treatment. J Drug Target. 24:492–502. 2016. View Article : Google Scholar
44	Goltz D, Gevensleben H, Dietrich J, Ellinger J, Landsberg J, Kristiansen G and Dietrich D: Promoter methylation of the immune checkpoint receptor PD-1 (PDCD1) is an independent prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients following radical prostatectomy. OncoImmunology. 5:e12215552016. View Article : Google Scholar :
45	Holmes EE, Goltz D, Sailer V, Jung M, Meller S, Uhl B, Dietrich J, Röhler M, Ellinger J, Kristiansen G, et al: PITX3 promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients after radical prostatectomy. Clin Epigenetics. 8:1042016. View Article : Google Scholar :
46	Meller S, Zipfel L, Gevensleben H, Dietrich J, Ellinger J, Majores M, Stein J, Sailer V, Jung M, Kristiansen G, et al: CDO1 promoter methylation is associated with gene silencing and is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients. Epigenetics. 11:871–880. 2016. View Article : Google Scholar : PubMed/NCBI
47	Gonzàlez-Porta M, Frankish A, Rung J, Harrow J and Brazma A: Transcriptome analysis of human tissues and cell lines reveals one dominant transcript per gene. Genome Biol. 14:R702013. View Article : Google Scholar : PubMed/NCBI
48	Soussi T, Leroy B and Taschner PE: Recommendations for analyzing and reporting TP53 gene variants in the high-throughput sequencing era. Hum Mutat. 35:766–778. 2014. View Article : Google Scholar : PubMed/NCBI
49	Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, Corey E, Nanus DM, Plymate SR and Giannakakou P: Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res. 74:2270–2282. 2014. View Article : Google Scholar : PubMed/NCBI
50	Carstens RP, Eaton JV, Krigman HR, Walther PJ and Garcia-Blanco MA: Alternative splicing of fibroblast growth factor receptor 2 (FGF-R2) in human prostate cancer. Oncogene. 15:3059–3065. 1997. View Article : Google Scholar
51	Anczuków O and Krainer AR: Splicing-factor alterations in cancers. RNA. 22:1285–1301. 2016. View Article : Google Scholar : PubMed/NCBI
52	Lee Y and Rio DC: Mechanisms and regulation of alternative Pre-mRNA splicing. Annu Rev Biochem. 84:291–323. 2015. View Article : Google Scholar : PubMed/NCBI