Elevated expression of the MYB proto-oncogene like 2 (MYBL2)-encoding gene as a prognostic and predictive biomarker in human cancers

Zekun Xin; Yang Li; Lingyin Meng; Lijun Dong; Jing Ren; Jianlong Men; Zekun Xin; Yang Li; Lingyin Meng; Lijun Dong; Jing Ren; Jianlong Men

doi:10.3934/mbe.2022085

Mathematical Biosciences and Engineering

2022, Volume 19, Issue 2: 1825-1842. doi: 10.3934/mbe.2022085

Previous Article Next Article

Research article Special Issues

Elevated expression of the MYB proto-oncogene like 2 (MYBL2)-encoding gene as a prognostic and predictive biomarker in human cancers

1.
Urology Surgery, Hebei Petro China Central Hospital, Langfang 065000, China
2.
Precision Medicine Center, Tianjin Medical University General Hospital, Tianjin 300000, China
3.
Central Laboratory, Linyi People's Hospital, Linyi 276000, China

Academic Editor: Xiangtao Li

Received: 10 October 2021 Accepted: 13 December 2021 Published: 17 December 2021

Recently, MYBL2 is frequently found to be overexpressed and associated with poor patient outcome in breast cancer, colorectal cancer, bladder carcinoma, hepatocellular carcinoma, neuroblastoma and acute myeloid leukemia. In view of the fact that there is an association between MYBL2 expression and the clinicopathological features of human cancers, most studies reported so far are limited in their sample size, tissue type and discrete outcomes. Furthermore, we need to verify which additional cancer entities are also affected by MYBL2 deregulation and which patients could specifically benefit from using MYBL2 as a biomarker or therapeutic target. We characterized the up-regulated expression level of MYBL2 in a large variety of human cancer via TCGA and oncomine database. Subsequently, we verified the elevated MYBL2 expression effect on clinical outcome using various databases. Then, we investigate the potential pathway in which MYBL2 may participate in and find 4 TFs (transcript factors) that may regulate MYBL2 expression using bioinformatic methods. At last, we confirmed elevated MYBL2 expression can be useful as a biomarker and potential therapeutic target of poor patient prognosis in a large variety of human cancers. Additionally, we find E2F1, E2F2, E2F7 and ZNF659 could interact with MYBL2 promotor directly or indirectly, indicating the four TFs may be the upstream regulator of MYBL2. TP53 mutation or TP53 signaling altered may lead to elevated MYBL2 expression. Our findings indicate that elevated MYBL2 expression represents a prognostic biomarker for a large number of cancers. What's more, patients with both P53 mutation and elevated MTBL2 expression showed a worse survival in PRAD and BRCA.
- MYBL2,
- biomarker,
- clinical outcome,
- human cancer,
- prognosis
Citation: Zekun Xin, Yang Li, Lingyin Meng, Lijun Dong, Jing Ren, Jianlong Men. Elevated expression of the MYB proto-oncogene like 2 (MYBL2)-encoding gene as a prognostic and predictive biomarker in human cancers[J]. Mathematical Biosciences and Engineering, 2022, 19(2): 1825-1842. doi: 10.3934/mbe.2022085

Related Papers:

Abstract

Recently, MYBL2 is frequently found to be overexpressed and associated with poor patient outcome in breast cancer, colorectal cancer, bladder carcinoma, hepatocellular carcinoma, neuroblastoma and acute myeloid leukemia. In view of the fact that there is an association between MYBL2 expression and the clinicopathological features of human cancers, most studies reported so far are limited in their sample size, tissue type and discrete outcomes. Furthermore, we need to verify which additional cancer entities are also affected by MYBL2 deregulation and which patients could specifically benefit from using MYBL2 as a biomarker or therapeutic target. We characterized the up-regulated expression level of MYBL2 in a large variety of human cancer via TCGA and oncomine database. Subsequently, we verified the elevated MYBL2 expression effect on clinical outcome using various databases. Then, we investigate the potential pathway in which MYBL2 may participate in and find 4 TFs (transcript factors) that may regulate MYBL2 expression using bioinformatic methods. At last, we confirmed elevated MYBL2 expression can be useful as a biomarker and potential therapeutic target of poor patient prognosis in a large variety of human cancers. Additionally, we find E2F1, E2F2, E2F7 and ZNF659 could interact with MYBL2 promotor directly or indirectly, indicating the four TFs may be the upstream regulator of MYBL2. TP53 mutation or TP53 signaling altered may lead to elevated MYBL2 expression. Our findings indicate that elevated MYBL2 expression represents a prognostic biomarker for a large number of cancers. What's more, patients with both P53 mutation and elevated MTBL2 expression showed a worse survival in PRAD and BRCA.

References

[1]	A. Sala, R. Watson, B-Myb protein in cellular proliferation, transcription control, and cancer: Latest developments, J. Cell. Physiol., 3 (1999), 245−250. doi: 10.1002/(SICI)1097-4652(199906)179:3<245:AID-JCP1>3.0.CO;2-H. doi: 10.1002/(SICI)1097-4652(199906)179:3<245:AID-JCP1>3.0.CO;2-H
[2]	M. Bessa, M. Joaquin, F. Tavner, M. K. Saville, R. J. Watson, Regulation of the cell cycle by B-Myb, Blood Cells Mol. Dis., 2 (2001), 416−421. doi: 10.1006/bcmd.2001.0399. doi: 10.1006/bcmd.2001.0399
[3]	K. V. Tarasov, Y. S. Tarasova, W. L. Tam, D. R. Riordon, S. T. Elliott, G. Kania, et al., B-MYB is essential for normal cell cycle progression and chromosomal stability of embryonic stem cells, PloS one, 6 (2008), e2478. doi: 10.1371/journal.pone.0002478. doi: 10.1371/journal.pone.0002478
[4]	S. Sadasivam, J. A. DeCaprio, The DREAM complex: master coordinator of cell cycle-dependent gene expression, Nat. Rev. Cancer, 8 (2013), 585−595. doi: 10.1038/nrc3556. doi: 10.1038/nrc3556
[5]	M. Joaquin, R. J. Watson, Cell cycle regulation by the B-Myb transcription factor, Cell. Mol. Life Sci., 11 (2003), 2389-2401. doi: 10.1007/s00018-003-3037-4. doi: 10.1007/s00018-003-3037-4
[6]	S. Sadasivam, S. Duan, J. A. DeCaprio, The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression, Genes Dev., 5 (2012), 474−489. doi: 10.110r1/gad.181933.111. doi: 10.110r1/gad.181933.111
[7]	R. Bayley, C. Ward, P. Garcia, MYBL2 amplification in breast cancer: Molecular mechanisms and therapeutic potential, Biochim. Biophys. Acta Rev. Cancer, 2020 (2020), 188407. doi: 10.1016/j.bbcan.2020.188407. doi: 10.1016/j.bbcan.2020.188407
[8]	F. Ren, L. Wang, X. Shen, X. Xiao, Z. Liu, P. Wei, et al., MYBL2 is an independent prognostic marker that has tumor-promoting functions in colorectal cancer, Am. J. Cancer Res., 4 (2015), 1542.
[9]	M. Zhang, H. Li, D. Zou, J. Gao, Ruguo key genes and tumor driving factors identification of bladder cancer based on the RNA-seq profile, Onco Targets Ther., 9 (2016), 2717. doi: 10.2147/ott.s92529. doi: 10.2147/ott.s92529
[10]	Z. Guan, W. Cheng, D. Huang, A. Wei, High MYBL2 expression and transcription regulatory activity is associated with poor overall survival in patients with hepatocellular carcinoma, Curr. Res. Transl. Med., 1 (2018), 27−32. doi: 10.1016/j.retram.2017.11.002. doi: 10.1016/j.retram.2017.11.002
[11]	G. Raschellà, V. Cesi, R. Amendola, A. Negroni, B. Tanno, P. Altavista, et al., Expression of B-myb in neuroblastoma tumors is a poor prognostic factor independent from MYCN amplification, Cancer Res., 14 (1999), 3365−3368.
[12]	O. Fuster, M. Llop, S. Dolz, P. Garcíab, E. Suchc, M. Ibáñez, et al., Adverse prognostic value of MYBL2 overexpression and association with microRNA-30 family in acute myeloid leukemia patients, Leuk. Res., 12 (2013), 1690−1696. doi: 10.1016/j.leukres.2013.09.015. doi: 10.1016/j.leukres.2013.09.015
[13]	S. A. Forbes, D. Beare, P. Gunasekaran, K. Leung, N. Bindal, H. Boutselakis, et al., COSMIC: exploring the world's knowledge of somatic mutations in human cancer, Nucleic Acids Res., D1 (2015), D805−D811. doi: 10.1093/nar/gku1075. doi: 10.1093/nar/gku1075
[14]	D. R. Rhodes, S. Kalyana-Sundaram, V. Mahavisno, R. Varambally, J. Yu, B. B. Briggs, et al., Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles, Neoplasia, 2 (2007), 166−180. doi: 10.1593/neo.07112. doi: 10.1593/neo.07112
[15]	J. Vivian, A. A. Rao, F. A. Nothaft, C. Ketchum, J. Armstrong, A. Novak, et al., Toil enables reproducible, open source, big biomedical data analyses, Nat. Biotechnol., 4 (2017), 314−316. doi: 10.1038/nbt.3772. doi: 10.1038/nbt.3772
[16]	J. Gao, B. A. Aksoy, U. G. Dogrusoz, Dresdner, B. Gross, S. O. Sumer, et al., Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal, Sci. Signal., 269 (2013), pl1−pl1. doi: 10.1126/scisignal.2004088. doi: 10.1126/scisignal.2004088
[17]	E. Cerami, J. Gao, U. Dogrusoz, B. E. Gross, S. O. Sumer, B. A. Aksoy, et al., The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data, Cancer Discov, 2 (2012). doi: 10.1158/2159-8290.CD-12-0095. doi: 10.1158/2159-8290.CD-12-0095
[18]	H. Mizuno, K. Kitada, K. Nakai, A. Sarai, PrognoScan: a new database for meta-analysis of the prognostic value of genes, BMC Med. Genomics, 1 (2009), 1−11. doi: 10.1186/1755-8794-2-18. doi: 10.1186/1755-8794-2-18
[19]	B. Györffy, A. Lanczky, A. C. Eklund, C. Denkert, J. Budczies, Q. Li, et al., An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients, Breast Cancer Res. Treat., 3 (2010), 725−731. doi: 10.1007/s10549-009-0674-9. doi: 10.1007/s10549-009-0674-9
[20]	S, R. Falcon, R. Gentleman, Using GOstats to test gene lists for GO term association, Bioinformatics, 2 (2007), 257−258. doi: 10.1093/bioinformatics/btl567. doi: 10.1093/bioinformatics/btl567
[21]	H. Hu, Y. R. Miao, L. H. Jia, Q. Y. Yu, Q. Zhang, A. Y. Guo, et al., AnimalTFDB 3.0: a comprehensive resource for annotation and prediction of animal transcription factors, Nucleic Acids Res., D1 (2019), D33−D38. doi: 10.1093/nar/gky822. doi: 10.1093/nar/gky822
[22]	P. Shannon, M. Richards, An annotated collection of protein-DNA binding sequence motifs, 2021. Available from: https://xueshu.baidu.com/usercenter/paper/show?paperid=73fac988c60c44137363f1c554acbdea.
[23]	H. Pagès, P. Aboyoun, R. Gentleman, S. DebRoy, Biostrings: Efficient manipulation of biological strings, Bioconductor, 2021 (2021). doi: 10.18129/B9.bioc.Biostrings. doi: 10.18129/B9.bioc.Biostrings
[24]	F. Bray, J. Ferlay, I. Soerjomataram, R. L. Siegel, L. A. Torre, A. Jema, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries, CA Cancer J. Clin., 6 (2018), 394−424. doi: 10.3322/caac.21492. doi: 10.3322/caac.21492
[25]	R. Zheng, C. Wan, S. Mei, Q. Qin, Q. Wu, H. Sun, et al., Cistrome Data Browser: expanded datasets and new tools for gene regulatory analysis, Nucleic Acids Res., D1 (2019), D729−D735. doi: 10.1093/nar/gky1094. doi: 10.1093/nar/gky1094
[26]	H. Nord, U. Segersten, J. Sandgren, K. Wester, C. Busch, U. Menzel, et al., Focal amplifications are associated with high grade and recurrences in stage Ta bladder carcinoma, Int. J. Cancer, 6 (2010), 1390−1402. doi: 10.1002/ijc.24954. doi: 10.1002/ijc.24954
[27]	K. Inoue, E. A. Fry, Novel molecular markers for breast cancer, Biomark. Cancer, 8 (2016), S38394. doi: 10.4137/BIC.S38394. doi: 10.4137/BIC.S38394
[28]	F. Ren, L. Wang, X. Shen, X. Xiao, Z. Liu, P. Wei, et al., MYBL2 is an independent prognostic marker that has tumor-promoting functions in colorectal cancer, Am. J. Cancer Res., 4 (2015), 1542.
[29]	H. D. Qin, X. Y. Liao, Y. B. Chen, S. Yi. Huang, W. Q. Xue, F. F. Li, et al., Genomic characterization of esophageal squamous cell carcinoma reveals critical genes underlying tumorigenesis and poor prognosis, Am. J. Hum. Genet., 4 (2016), 709−727. doi: 10.1016/j.ajhg.2016.02.021. doi: 10.1016/j.ajhg.2016.02.021
[30]	J. Musa, M. M. Aynaud, O. Mirabeau, O. Delattre, T. G. Grünewald, MYBL2 (B-Myb): a central regulator of cell proliferation, cell survival and differentiation involved in tumorigenesis, Cell Death Dis., 6 (2017), e2895−e2895. doi: 10.1038/cddis.2017.244. doi: 10.1038/cddis.2017.244
[31]	M. Fischer, M. Quaas, L. Steiner, The p53-p21-DREAM-CDE/CHR pathway regulates G2/M cell cycle genes, Nucleic Acids Res., 1 (2016), 164−174. doi: 10.1093/nar/gkv927. doi: 10.1093/nar/gkv927
[32]	Bioconductor package maintainer, Finding candidate binding sites for known transcription factors via sequence matching, Bioconductor, 2018 (2018). doi: 10.18129/B9.bioc.generegulation. doi: 10.18129/B9.bioc.generegulation
[33]	X. Zhao, X. Li, Z. Ma, M. H. Yin, Identify DNA-binding proteins with optimal Chou's amino acid composition, Protein Pept. Lett., 4 (2012), 398−405. doi: 10.2174/092986612799789404. doi: 10.2174/092986612799789404
[34]	Y. Wang, Z. Ma, K. C. Wong, X. Li, Nature-inspired multiobjective patient stratification from cancer gene expression data, Inf. Sci., 526 (2020), 245−262. doi: 10.1016/j.ins.2020.03.095. doi: 10.1016/j.ins.2020.03.095
[35]	Y. Wang, B. Liu, Z. Ma, K. C. Wong, X. Li, Nature-inspired multiobjective cancer subtype diagnosis, IEEE J. Transl. Eng. Health Med., 7 (2019), 1−12. doi: 10.1109/jtehm.2019.2891746. doi: 10.1109/jtehm.2019.2891746
[36]	Y. Wang, Z. Ma, K. C. Wong, X. Li, Evolving multiobjective cancer subtype diagnosis from cancer gene expression data, IEEE/ACM Trans. Comput. Biol. Bioinform., 6 (2020), 2431−2444. doi: 10.1109/tcbb.2020.2974953. doi: 10.1109/tcbb.2020.2974953

mbe-19-02-085-supplementary.pdf

Reader Comments

Your name:*

Email:*
© 2022 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)