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Published in: World Journal of Surgical Oncology 1/2023

Open Access 01-12-2023 | Urothelial Cancer | Research

Low expression of ZSCAN4 predicts unfavorable outcome in urothelial carcinoma of upper urinary tract and urinary bladder

Authors: Hong-Lin He, Hong-Yue Lai, Ti-Chun Chan, Chung-Hsi Hsing, Steven K. Huang, Kun-Lin Hsieh, Tzu-Ju Chen, Wan-Shan Li, Yu-Hsuan Kuo, Yow-Ling Shiue, Chien-Feng Li

Published in: World Journal of Surgical Oncology | Issue 1/2023

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Abstract

Background

With the advance in genome-wide analyses, genetic alternations have been found to play an important role in carcinogenesis and aggressiveness of UC. Through bioinformatic analysis of gene expression profiles of urinary bladder urothelial carcinoma (UBUC) from publicly available GEO dataset (GSE31684), Zinc finger and SCAN domain containing 4 (ZSCAN4) was identified as a significant downregulated gene in muscle-invasive bladder cancer when compared with non-muscle-invasive bladder cancer.

Methods

The expression of ZSCAN4 was evaluated by immunohistochemistry in 340 upper urinary tract urothelial carcinomas (UTUCs) and 295 UBUCs. The expression profiles of ZSCAN4 and potential signaling pathways were analyzed bioinformatically.

Results

In UTUC, low expression of ZSCAN4 was significantly associated with advanced primary pT stage (P = 0.011), increased nodal metastasis (P = 0.002) and increased vascular invasion (P = 0.019). In UBUC, low expression of ZSCAN4 was significantly correlated with advanced primary pT stage (P < 0.001), increased nodal metastasis (P = 0.001), high histological grade (P = 0.003) and increased vascular invasion (P = 0.003). In survival analysis, low expression of ZSCAN4 acted as an independent negative prognostic factor for disease-specific survival and metastasis-free survival both in UTUC and UBUC. Gene ontology analysis showed that ZSCAN4 mRNA and its co-downregulated genes are associated with the mitotic cell cycle.

Conclusions

Low expression of ZSCAN4 predicted worse outcome in urothelial carcinoma and might have potential regulatory role in cell mitosis.
Appendix
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Literature
1.
go back to reference Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15:25–41.CrossRefPubMed Knowles MA, Hurst CD. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat Rev Cancer. 2015;15:25–41.CrossRefPubMed
2.
go back to reference Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.CrossRef Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.CrossRef
3.
go back to reference Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, Roth B, Cheng T, Tran M, Lee IL, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25:152–65.CrossRefPubMedPubMedCentral Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, Roth B, Cheng T, Tran M, Lee IL, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25:152–65.CrossRefPubMedPubMedCentral
4.
go back to reference Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE, Yeh JJ, Milowsky MI, Iyer G, Parker JS, Kim WY. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A. 2014;111:3110–5.CrossRefPubMedPubMedCentral Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, Wobker SE, Yeh JJ, Milowsky MI, Iyer G, Parker JS, Kim WY. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci U S A. 2014;111:3110–5.CrossRefPubMedPubMedCentral
5.
go back to reference Sjodahl G, Lauss M, Lovgren K, Chebil G, Gudjonsson S, Veerla S, Patschan O, Aine M, Ferno M, Ringner M, et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res. 2012;18:3377–86.CrossRefPubMed Sjodahl G, Lauss M, Lovgren K, Chebil G, Gudjonsson S, Veerla S, Patschan O, Aine M, Ferno M, Ringner M, et al. A molecular taxonomy for urothelial carcinoma. Clin Cancer Res. 2012;18:3377–86.CrossRefPubMed
6.
go back to reference Cairns P, Mao L, Merlo A, Lee DJ, Schwab D, Eby Y, Tokino K, van der Riet P, Blaugrund JE, Sidransky D. Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science. 1994;265:415–7.CrossRefPubMed Cairns P, Mao L, Merlo A, Lee DJ, Schwab D, Eby Y, Tokino K, van der Riet P, Blaugrund JE, Sidransky D. Rates of p16 (MTS1) mutations in primary tumors with 9p loss. Science. 1994;265:415–7.CrossRefPubMed
7.
go back to reference Williamson MP, Elder PA, Shaw ME, Devlin J, Knowles MA. p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. Hum Mol Genet. 1995;4:1569–77.CrossRefPubMed Williamson MP, Elder PA, Shaw ME, Devlin J, Knowles MA. p16 (CDKN2) is a major deletion target at 9p21 in bladder cancer. Hum Mol Genet. 1995;4:1569–77.CrossRefPubMed
8.
go back to reference Aboulkassim TO, LaRue H, Lemieux P, Rousseau F, Fradet Y. Alteration of the PATCHED locus in superficial bladder cancer. Oncogene. 2003;22:2967–71.CrossRefPubMed Aboulkassim TO, LaRue H, Lemieux P, Rousseau F, Fradet Y. Alteration of the PATCHED locus in superficial bladder cancer. Oncogene. 2003;22:2967–71.CrossRefPubMed
9.
go back to reference McGarvey TW, Maruta Y, Tomaszewski JE, Linnenbach AJ, Malkowicz SB. PTCH gene mutations in invasive transitional cell carcinoma of the bladder. Oncogene. 1998;17:1167–72.CrossRefPubMed McGarvey TW, Maruta Y, Tomaszewski JE, Linnenbach AJ, Malkowicz SB. PTCH gene mutations in invasive transitional cell carcinoma of the bladder. Oncogene. 1998;17:1167–72.CrossRefPubMed
10.
go back to reference Nishiyama H, Hornigold N, Davies AM, Knowles MA. A sequence-ready 840-kb PAC contig spanning the candidate tumor suppressor locus DBC1 on human chromosome 9q32-q33. Genomics. 1999;59:335–8.CrossRefPubMed Nishiyama H, Hornigold N, Davies AM, Knowles MA. A sequence-ready 840-kb PAC contig spanning the candidate tumor suppressor locus DBC1 on human chromosome 9q32-q33. Genomics. 1999;59:335–8.CrossRefPubMed
11.
go back to reference Sjodahl G, Lauss M, Gudjonsson S, Liedberg F, Hallden C, Chebil G, Mansson W, Hoglund M, Lindgren D. A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1. PLoS ONE. 2011;6:e18583.CrossRefPubMedPubMedCentral Sjodahl G, Lauss M, Gudjonsson S, Liedberg F, Hallden C, Chebil G, Mansson W, Hoglund M, Lindgren D. A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1. PLoS ONE. 2011;6:e18583.CrossRefPubMedPubMedCentral
12.
go back to reference Kompier LC, Lurkin I, van der Aa MN, van Rhijn BW, van der Kwast TH, Zwarthoff EC. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS ONE. 2010;5:e13821.CrossRefPubMedPubMedCentral Kompier LC, Lurkin I, van der Aa MN, van Rhijn BW, van der Kwast TH, Zwarthoff EC. FGFR3, HRAS, KRAS, NRAS and PIK3CA mutations in bladder cancer and their potential as biomarkers for surveillance and therapy. PLoS ONE. 2010;5:e13821.CrossRefPubMedPubMedCentral
13.
go back to reference Lopez-Knowles E, Hernandez S, Malats N, Kogevinas M, Lloreta J, Carrato A, Tardon A, Serra C, Real FX. PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 2006;66:7401–4.CrossRefPubMed Lopez-Knowles E, Hernandez S, Malats N, Kogevinas M, Lloreta J, Carrato A, Tardon A, Serra C, Real FX. PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 2006;66:7401–4.CrossRefPubMed
14.
go back to reference Mitra AP, Cote RJ. Molecular pathogenesis and diagnostics of bladder cancer. Annu Rev Pathol. 2009;4:251–85.CrossRefPubMed Mitra AP, Cote RJ. Molecular pathogenesis and diagnostics of bladder cancer. Annu Rev Pathol. 2009;4:251–85.CrossRefPubMed
15.
go back to reference Mitra AP, Datar RH, Cote RJ. Molecular pathways in invasive bladder cancer: new insights into mechanisms, progression, and target identification. J Clin Oncol. 2006;24:5552–64.CrossRefPubMed Mitra AP, Datar RH, Cote RJ. Molecular pathways in invasive bladder cancer: new insights into mechanisms, progression, and target identification. J Clin Oncol. 2006;24:5552–64.CrossRefPubMed
16.
go back to reference Sanchez-Carbayo M, Socci ND, Charytonowicz E, Lu M, Prystowsky M, Childs G, Cordon-Cardo C. Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes. Cancer Res. 2002;62:6973–80.PubMed Sanchez-Carbayo M, Socci ND, Charytonowicz E, Lu M, Prystowsky M, Childs G, Cordon-Cardo C. Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes. Cancer Res. 2002;62:6973–80.PubMed
17.
18.
go back to reference Riester M, Taylor JM, Feifer A, Koppie T, Rosenberg JE, Downey RJ, Bochner BH, Michor F. Combination of a novel gene expression signature with a clinical nomogram improves the prediction of survival in high-risk bladder cancer. Clin Cancer Res. 2012;18:1323–33.CrossRefPubMedPubMedCentral Riester M, Taylor JM, Feifer A, Koppie T, Rosenberg JE, Downey RJ, Bochner BH, Michor F. Combination of a novel gene expression signature with a clinical nomogram improves the prediction of survival in high-risk bladder cancer. Clin Cancer Res. 2012;18:1323–33.CrossRefPubMedPubMedCentral
19.
go back to reference Lee HY, Yeh BW, Chan TC, Yang KF, Li WM, Huang CN, Ke HL, Li CC, Yeh HC, Liang PI, et al. Sulfatase-1 overexpression indicates poor prognosis in urothelial carcinoma of the urinary bladder and upper tract. Oncotarget. 2017;8:47216–29.CrossRefPubMedPubMedCentral Lee HY, Yeh BW, Chan TC, Yang KF, Li WM, Huang CN, Ke HL, Li CC, Yeh HC, Liang PI, et al. Sulfatase-1 overexpression indicates poor prognosis in urothelial carcinoma of the urinary bladder and upper tract. Oncotarget. 2017;8:47216–29.CrossRefPubMedPubMedCentral
20.
go back to reference Zalzman M, Falco G, Sharova LV, Nishiyama A, Thomas M, Lee SL, Stagg CA, Hoang HG, Yang HT, Indig FE, et al. Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature. 2010;464:858–63.CrossRefPubMedPubMedCentral Zalzman M, Falco G, Sharova LV, Nishiyama A, Thomas M, Lee SL, Stagg CA, Hoang HG, Yang HT, Indig FE, et al. Zscan4 regulates telomere elongation and genomic stability in ES cells. Nature. 2010;464:858–63.CrossRefPubMedPubMedCentral
21.
go back to reference Falco G, Lee SL, Stanghellini I, Bassey UC, Hamatani T, Ko MS. Zscan4: a novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Dev Biol. 2007;307:539–50.CrossRefPubMedPubMedCentral Falco G, Lee SL, Stanghellini I, Bassey UC, Hamatani T, Ko MS. Zscan4: a novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells. Dev Biol. 2007;307:539–50.CrossRefPubMedPubMedCentral
22.
go back to reference Jiang J, Lv W, Ye X, Wang L, Zhang M, Yang H, Okuka M, Zhou C, Zhang X, Liu L, Li J. Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation. Cell Res. 2013;23:92–106.CrossRefPubMed Jiang J, Lv W, Ye X, Wang L, Zhang M, Yang H, Okuka M, Zhou C, Zhang X, Liu L, Li J. Zscan4 promotes genomic stability during reprogramming and dramatically improves the quality of iPS cells as demonstrated by tetraploid complementation. Cell Res. 2013;23:92–106.CrossRefPubMed
23.
go back to reference Thool M, Sundaravadivelu PK, Sudhagar S, Thummer RP. A comprehensive review on the role of ZSCAN4 in embryonic development, stem cells, and cancer. Stem Cell Reviews and Reports. 2022;18:2740–56.CrossRefPubMed Thool M, Sundaravadivelu PK, Sudhagar S, Thummer RP. A comprehensive review on the role of ZSCAN4 in embryonic development, stem cells, and cancer. Stem Cell Reviews and Reports. 2022;18:2740–56.CrossRefPubMed
24.
go back to reference McKinnon PJ, Caldecott KW. DNA strand break repair and human genetic disease. Annu Rev Genomics Hum Genet. 2007;8:37–55.CrossRefPubMed McKinnon PJ, Caldecott KW. DNA strand break repair and human genetic disease. Annu Rev Genomics Hum Genet. 2007;8:37–55.CrossRefPubMed
25.
go back to reference Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, Wu JR. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A. 1988;85:6622–6.CrossRefPubMedPubMedCentral Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, Wu JR. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A. 1988;85:6622–6.CrossRefPubMedPubMedCentral
26.
go back to reference Thanasoula M, Escandell JM, Martinez P, Badie S, Munoz P, Blasco MA, Tarsounas M. p53 prevents entry into mitosis with uncapped telomeres. Curr Biol. 2010;20:521–6.CrossRefPubMedPubMedCentral Thanasoula M, Escandell JM, Martinez P, Badie S, Munoz P, Blasco MA, Tarsounas M. p53 prevents entry into mitosis with uncapped telomeres. Curr Biol. 2010;20:521–6.CrossRefPubMedPubMedCentral
28.
go back to reference Hockemeyer D, Daniels JP, Takai H, de Lange T. Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres. Cell. 2006;126:63–77.CrossRefPubMed Hockemeyer D, Daniels JP, Takai H, de Lange T. Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres. Cell. 2006;126:63–77.CrossRefPubMed
29.
30.
go back to reference Portney BA, Arad M, Gupta A, Brown RA, Khatri R, Lin PN, Hebert AM, Angster KH, Silipino LE, Meltzer WA, et al. ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype. Oncogene. 2020;39:4970–82.CrossRefPubMedPubMedCentral Portney BA, Arad M, Gupta A, Brown RA, Khatri R, Lin PN, Hebert AM, Angster KH, Silipino LE, Meltzer WA, et al. ZSCAN4 facilitates chromatin remodeling and promotes the cancer stem cell phenotype. Oncogene. 2020;39:4970–82.CrossRefPubMedPubMedCentral
31.
go back to reference Zhang B, Fu D, Xu Q, Cong X, Wu C, Zhong X, Ma Y, Lv Z, Chen F, Han L, et al. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat Commun. 2018;9:1723.CrossRefPubMedPubMedCentral Zhang B, Fu D, Xu Q, Cong X, Wu C, Zhong X, Ma Y, Lv Z, Chen F, Han L, et al. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat Commun. 2018;9:1723.CrossRefPubMedPubMedCentral
32.
go back to reference Zaleski M, Gogoj A, Walter V, Raman JD, Kaag M, Merrill SB, Drabick J, Joshi M, Holder S, DeGraff DJ, Warrick JI. Mitotic activity in noninvasive papillary urothelial carcinoma: its value in predicting tumor recurrence and comparison with the contemporary 2-tier grading system. Hum Pathol. 2019;84:275–82.CrossRefPubMed Zaleski M, Gogoj A, Walter V, Raman JD, Kaag M, Merrill SB, Drabick J, Joshi M, Holder S, DeGraff DJ, Warrick JI. Mitotic activity in noninvasive papillary urothelial carcinoma: its value in predicting tumor recurrence and comparison with the contemporary 2-tier grading system. Hum Pathol. 2019;84:275–82.CrossRefPubMed
34.
go back to reference Prosser SL, Pelletier L. Mitotic spindle assembly in animal cells: a fine balancing act. Nat Rev Mol Cell Biol. 2017;18:187–201.CrossRefPubMed Prosser SL, Pelletier L. Mitotic spindle assembly in animal cells: a fine balancing act. Nat Rev Mol Cell Biol. 2017;18:187–201.CrossRefPubMed
Metadata
Title
Low expression of ZSCAN4 predicts unfavorable outcome in urothelial carcinoma of upper urinary tract and urinary bladder
Authors
Hong-Lin He
Hong-Yue Lai
Ti-Chun Chan
Chung-Hsi Hsing
Steven K. Huang
Kun-Lin Hsieh
Tzu-Ju Chen
Wan-Shan Li
Yu-Hsuan Kuo
Yow-Ling Shiue
Chien-Feng Li
Publication date
01-12-2023
Publisher
BioMed Central
Published in
World Journal of Surgical Oncology / Issue 1/2023
Electronic ISSN: 1477-7819
DOI
https://doi.org/10.1186/s12957-023-02948-4

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