Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2021

Open Access 01-12-2021 | Prostate Cancer | Research

High copy number variations, particular transcription factors, and low immunity contribute to the stemness of prostate cancer cells

Authors: Zao Dai, Ping Liu

Published in: Journal of Translational Medicine | Issue 1/2021

Login to get access

Abstract

Background

Tumor metastasis is the main cause of death of cancer patients, and cancer stem cells (CSCs) is the basis of tumor metastasis. However, systematic analysis of the stemness of prostate cancer cells is still not abundant. In this study, we explore the effective factors related to the stemness of prostate cancer cells by comprehensively mining the multi-omics data from TCGA database.

Methods

Based on the prostate cancer transcriptome data in TCGA, gene expression modules that strongly relate to the stemness of prostate cancer cells are obtained with WGCNA and stemness scores. Copy number variation of stemness genes of prostate cancer is calculated and the difference of transcription factors between prostate cancer and normal tissues is evaluated by using CNV (copy number variation) data and ATAC-seq data. The protein interaction network of stemness genes in prostate cancer is constructed using the STRING database. Meanwhile, the correlation between stemness genes of prostate cancer and immune cells is analyzed.

Results

Prostate cancer with higher Gleason grade possesses higher cell stemness. The gene set highly related to prostate cancer stemness has higher CNV in prostate cancer samples than that in normal samples. Although the transcription factors of stemness genes have similar expressions, they have different contributions between normal and prostate cancer tissues; and particular transcription factors enhance the stemness of prostate cancer, such as PUM1, CLOCK, SP1, TCF12, and so on. In addition, the lower tumor immune microenvironment is conducive to the stemness of prostate cancer. CD8 + T cells and M1 macrophages may play more important role in the stemness of prostate cancer than other immune cells in the tumor microenvironment. Finally, EZH2 is found to play a central role in stemness genes and is negatively correlated with resting mast cells and positively correlated with activated memory CD4 + T cells.

Conclusions

Based on the systematic and combined analysis of multi-omics data, we find that high copy number variation, specific transcription factors, and low immune microenvironment jointly contribute to the stemness of prostate cancer cells. These findings may provide us new clues and directions for the future research on stemness of prostate cancer.
Appendix
Available only for authorised users
Literature
1.
2.
Malta TM, Sokolov A, Gentles AJ, Burzykowski T, Poisson L, Weinstein JN, Kaminska B, Huelsken J, Omberg L, Gevaert O, et al. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell. 2018;173:338-354 e315.PubMedPubMedCentralCrossRef
3.
4.
5.
Mei W, Lin X, Kapoor A, Gu Y, Zhao K, Tang D. The contributions of prostate cancer stem cells in prostate cancer initiation and metastasis. Cancers. 2019;11:434.PubMedCentralCrossRef
6.
Liao C-P, Adisetiyo H, Liang M, Roy-Burman P. Cancer Stem cells and microenvironment in prostate cancer progression. Hormones Cancer. 2010;1:297–305.PubMedCrossRef
7.
Krueger TE, Thorek DLJ, Meeker AK, Isaacs JT, Brennen WN. Tumor-infiltrating mesenchymal stem cells: Drivers of the immunosuppressive tumor microenvironment in prostate cancer? Prostate. 2019;79:320–30.PubMedCrossRef
8.
Wang W, Green M, Choi JE, Gijón M, Kennedy PD, Johnson JK, Liao P, Lang X, Kryczek I, Sell A, et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4.PubMedPubMedCentralCrossRef
9.
10.
Ihle CL, Owens P. Integrating the immune microenvironment of prostate cancer induced bone disease. Mol Carcinog. 2020;59:822–9.PubMedCrossRef
11.
12.
Weng CC, Ding PY, Liu YH, Hawse JR, Subramaniam M, Wu CC, Lin YC, Chen CY, Hung WC, Cheng KH. Mutant Kras-induced upregulation of CD24 enhances prostate cancer stemness and bone metastasis. Oncogene. 2019;38:2005–19.PubMedCrossRef
13.
Pai VC, Hsu CC, Chan TS, Liao WY, Chuu CP, Chen WY, Li CR, Lin CY, Huang SP, Chen LT, Tsai KK. ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-beta-catenin signaling. Oncogene. 2019;38:1340–53.PubMedCrossRef
14.
Xu N, Wu YP, Yin HB, Xue XY, Gou X. Molecular network-based identification of competing endogenous RNAs and mRNA signatures that predict survival in prostate cancer. J Transl Med. 2018;16:274.PubMedPubMedCentralCrossRef
15.
Zhu X, Gou X, Zhou M. Nomograms predict survival advantages of gleason score 3+4 Over 4+3 for prostate cancer: a SEER-based study. Front Oncol. 2019;9:646.PubMedPubMedCentralCrossRef
16.
Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.CrossRef
17.
He Z, Tang F, Lu Z, Huang Y, Lei H, Li Z, Zeng G. Analysis of differentially expressed genes, clinical value and biological pathways in prostate cancer. Am J Transl Res. 2018;10:1444–56.PubMedPubMedCentral
18.
He Z, Duan X, Zeng G. Identification of potential biomarkers and pivotal biological pathways for prostate cancer using bioinformatics analysis methods. PeerJ. 2019;7:e7872.PubMedPubMedCentralCrossRef
19.
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformat. 2008;9:559.CrossRef
20.
Kim D, Paggi JM, Park C, Bennett C, Salzberg SL. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol. 2019;37:907–15.PubMedPubMedCentralCrossRef
21.
Anders S, Pyl PT, Huber W. HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.PubMedCrossRef
22.
Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC20 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12:41.CrossRef
23.
24.
Ramírez F, Dündar F, Diehl S, Grüning BA, Manke T. deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 2014;42:W187–91.PubMedPubMedCentralCrossRef
25.
Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, Nusbaum C, Myers RM, Brown M, Li W, Liu XS. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.PubMedPubMedCentralCrossRef
26.
Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38:576–89.PubMedPubMedCentralCrossRef
27.
Phanstiel DH, Boyle AP, Araya CL, Snyder MP, Sushi R. flexible, quantitative and integrative genomic visualizations for publication-quality multi-panel figures. Bioinformatics. 2014;30:2808–10.PubMedPubMedCentralCrossRef
28.
Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, Treviño V, Shen H, Laird PW, Levine DA, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4:2612.PubMedCrossRef
29.
Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, Hoang CD, Diehn M, Alizadeh AA. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12:453–7.PubMedPubMedCentralCrossRef
30.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.PubMedPubMedCentralCrossRef
31.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.PubMedPubMedCentral
32.
Miranda A, Hamilton PT, Zhang AW, Pattnaik S, Becht E, Mezheyeuski A, Bruun J, Micke P, de Reynies A, Nelson BH. Cancer stemness, intratumoral heterogeneity, and immune response across cancers. Proc Natl Acad Sci. 2019;116:9020.PubMedCrossRefPubMedCentral
33.
Gorodetska I, Lukiyanchuk V, Peitzsch C, Kozeretska I, Dubrovska A. BRCA1 and EZH2 cooperate in regulation of prostate cancer stem cell phenotype. Int J Cancer. 2019;145:2974–85.PubMedCrossRef
34.
Song I-S, Jeong YJ, Jeong SH, Heo HJ, Kim HK, Bae KB, Park Y-H, Kim SU, Kim J-M, Kim N, et al. FOXM1-Induced PRX3 regulates stemness and survival of colon cancer cells via maintenance of mitochondrial function. Gastroenterology. 2015;149:1006-1016.e1009.PubMedCrossRef
35.
Zhang Q, Huang H, Liu A, Li J, Liu C, Sun B, Chen L, Gao Y, Xu D, Su C. Cell division cycle 20 (CDC20) drives prostate cancer progression via stabilization of β-catenin in cancer stem-like cells. EBioMedicine. 2019;42:397–407.PubMedPubMedCentralCrossRef
36.
Dai C, Miao CX, Xu XM, Liu LJ, Gu YF, Zhou D, Chen LS, Lin G, Lu GX. Transcriptional activation of human CDCA8 gene regulated by transcription factor NF-Y in embryonic stem cells and cancer cells. J Biol Chem. 2015;290:22423–34.PubMedPubMedCentralCrossRef
37.
Naef V, Monticelli S, Corsinovi D, Mazzetto MT, Cellerino A, Ori M. The age-regulated zinc finger factor ZNF367 is a new modulator of neuroblast proliferation during embryonic neurogenesis. Sci Rep. 2018;8:11836.PubMedPubMedCentralCrossRef
38.
Hu R, Wang MQ, Niu WB, Wang YJ, Liu YY, Liu LY, Wang M, Zhong J, You HY, Wu XH, et al. SKA3 promotes cell proliferation and migration in cervical cancer by activating the PI3K/Akt signaling pathway. Cancer Cell Int. 2018;18:183.PubMedPubMedCentralCrossRef
39.
Taniuchi K, Furihata M, Iwasaki S, Tanaka K, Shimizu T, Saito M, Saibara T. RUVBL1 directly binds actin filaments and induces formation of cell protrusions to promote pancreatic cancer cell invasion. Int J Oncol. 2014;44:1945–54.PubMedCrossRef
40.
Bereshchenko O, Mancini E, Luciani L, Gambardella A, Riccardi C, Nerlov C. Pontin is essential for murine hematopoietic stem cell survival. Haematologica. 2012;97:1291–4.PubMedPubMedCentralCrossRef
41.
Liu M, Hu Q, Tu M, Wang X, Yang Z, Yang G, Luo R. MCM6 promotes metastasis of hepatocellular carcinoma via MEK/ERK pathway and serves as a novel serum biomarker for early recurrence. J Exp Clin Cancer Res. 2018;37:10.PubMedPubMedCentralCrossRef
42.
Barton KM, Levine EM. Expression patterns and cell cycle profiles of PCNA, MCM6, cyclin D1, cyclin A2, cyclin B1, and phosphorylated histone H3 in the developing mouse retina. Dev Dyn. 2008;237:672–82.PubMedCrossRef
43.
Tomonaga T, Matsushita K, Ishibashi M, Nezu M, Shimada H, Ochiai T, Yoda K, Nomura F. Centromere protein H is up-regulated in primary human colorectal cancer and its overexpression induces aneuploidy. Cancer Res. 2005;65:4683–9.PubMedCrossRef
44.
Zhang JP, Zhang H, Wang HB, Li YX, Liu GH, Xing S, Li MZ, Zeng MS. Down-regulation of Sp1 suppresses cell proliferation, clonogenicity and the expressions of stem cell markers in nasopharyngeal carcinoma. J Transl Med. 2014;12:222.PubMedPubMedCentralCrossRef
45.
Zhao WF, Wang HB, Xie B, Hu LJ, Xu LH, Kuang BH, Li MZ, Zhang X. Sp1 and Sp3 are involved in the full transcriptional activity of centromere protein H in human nasopharyngeal carcinoma cells. FEBS J. 2012;279:2714–26.PubMedCrossRef
46.
Uyhazi KE, Yang Y, Liu N, Qi H, Huang XA, Mak W, Weatherbee SD, Song X, Lin H. Pumilio proteins exert distinct biological functions and multiple modes of post-transcriptional regulation in embryonic stem cell pluripotency and early embryogenesis. BioRxiv. 2019. https://​doi.​org/​10.​1101/​751909.CrossRef
47.
Guan X, Chen S, Liu Y. Wang L-l, Zhao Y, Zong Z-H: PUM1 promotes ovarian cancer proliferation, migration and invasion. Biochem Biophys Res Commun. 2018;497:313–8.PubMedCrossRef
48.
Janich P, Pascual G, Merlos-Suárez A, Batlle E, Ripperger J, Albrecht U. Cheng H-YM, Obrietan K, Di Croce L, Benitah SA: The circadian molecular clock creates epidermal stem cell heterogeneity. Nature. 2011;480:209–14.PubMedCrossRef
49.
Gambara G, Desideri M, Stoppacciaro A, Padula F, De Cesaris P, Starace D, Tubaro A, del Bufalo D, Filippini A, Ziparo E, Riccioli A. TLR3 engagement induces IRF-3-dependent apoptosis in androgen-sensitive prostate cancer cells and inhibits tumour growth in vivo. J Cell Mol Med. 2015;19:327–39.PubMedCrossRef
50.
Blum R, Gupta R, Burger PE, Ontiveros CS, Salm SN, Xiong X, Kamb A, Wesche H, Marshall L, Cutler G, et al. Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer. PLoS ONE. 2009;4:e5722.PubMedPubMedCentralCrossRef
51.
Wouters MCA, Nelson BH. Prognostic significance of tumor-infiltrating b cells and plasma cells in human cancer. Clin Cancer Res. 2018;24:6125.PubMedCrossRef
52.
Arco A, Edgar BA, Erhardt S. In vivo analysis of centromeric proteins reveals a stem cell-specific asymmetry and an essential role in differentiated, non-proliferating cells. Cell Rep. 2018;22:1982–93.CrossRef
53.
Behnan J, Grieg Z, Joel M, Ramsness I, Stangeland B. Gene knockdown of CENPA reduces sphere forming ability and stemness of glioblastoma initiating cells. Neuroepigenetics. 2016;7:6–18.CrossRef
54.
55.
Hsieh M-H, Chen Y-T, Chen Y-T, Lee Y-H, Lu J, Chien C-L, Chen H-F, Ho H-N, Yu C-J, Wang Z-Q, Teng S-C. PARP1 controls KLF4-mediated telomerase expression in stem cells and cancer cells. Nucleic Acids Res. 2017;45:10492–503.PubMedPubMedCentralCrossRef
56.
Sharonov GV, Serebrovskaya EO, Yuzhakova DV, Britanova OV, Chudakov DM. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat Rev Immunol. 2020;20:294–307.PubMedCrossRef
57.
Horning AM, Wang Y, Lin CK, Louie AD, Jadhav RR, Hung CN, Wang CM, Lin CL, Kirma NB, Liss MA, et al. Single-Cell RNA-seq reveals a subpopulation of prostate cancer cells with enhanced cell-cycle-related transcription and attenuated androgen response. Cancer Res. 2018;78:853–64.PubMedCrossRef
58.
59.
Lin D, Lin B, Bhanot H, Riou R, Abt NB, Rajagopal J, Saladi SV. RUVBL1 is an amplified epigenetic factor promoting proliferation and inhibiting differentiation program in head and neck squamous cancers. Oral Oncol. 2020;111:104930.PubMedCrossRef
60.
Bayley R, Blakemore D, Cancian L, Dumon S, Volpe G, Ward C, Almaghrabi R, Gujar J, Reeve N, Raghavan M, et al. MYBL2 supports DNA double strand break repair in hematopoietic stem cells. Cancer Res. 2018;78:5767–79.PubMed
61.
Musa J, Aynaud MM, Mirabeau O, Delattre O, Grunewald TG. MYBL2 (B-Myb): a central regulator of cell proliferation, cell survival and differentiation involved in tumorigenesis. Cell Death Dis. 2017;8:e2895.PubMedPubMedCentralCrossRef
62.
Nakajima T, Yasui K, Zen K, Inagaki Y, Fujii H, Minami M, Tanaka S, Taniwaki M, Itoh Y, Arii S, et al. Activation of B-Myb by E2F1 in hepatocellular carcinoma. Hepatol Res. 2008;38:886–95.PubMed
63.
Shin J, Kim TW, Kim H, Kim HJ, Suh MY, Lee S, Lee HT, Kwak S, Lee SE, Lee JH, et al. Aurkb/PP1-mediated resetting of Oct4 during the cell cycle determines the identity of embryonic stem cells. Elife. 2016;5:e10877.PubMedPubMedCentralCrossRef
64.
Hegyi K, Egervari K, Sandor Z, Mehes G. Aurora kinase B expression in breast carcinoma: cell kinetic and genetic aspects. Pathobiology. 2012;79:314–22.PubMedCrossRef
65.
Naudin C, Hattabi A, Michelet F, Miri-Nezhad A, Benyoucef A, Pflumio F, Guillonneau F, Fichelson S, Vigon I, Dusanter-Fourt I, Lauret E. PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells. Blood. 2017;129:2493–506.PubMedPubMedCentralCrossRef
66.
Dong Z, Zhang G, Qu M, Gimple RC, Wu Q, Qiu Z, Prager BC, Wang X, Kim LJY, Morton AR, et al. Targeting glioblastoma stem cells through disruption of the circadian clock. Cancer Discov. 2019;9:1556–73.PubMedPubMedCentralCrossRef
67.
Ashida S, Kawada C, Inoue K. Stromal regulation of prostate cancer cell growth by mevalonate pathway enzymes HMGCS1 and HMGCR. Oncol Lett. 2017;14:6533–42.PubMedPubMedCentral
68.
Assmann N, O’Brien KL, Donnelly RP, Dyck L, Zaiatz-Bittencourt V, Loftus RM, Heinrich P, Oefner PJ, Lynch L, Gardiner CM, et al. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat Immunol. 2017;18:1197–206.PubMedCrossRef
69.
Watson GW, Wickramasekara S, Palomera-Sanchez Z, Black C, Maier CS, Williams DE, Dashwood RH, Ho E. SUV39H1/H3K9me3 attenuates sulforaphane-induced apoptotic signaling in PC3 prostate cancer cells. Oncogenesis. 2014;3:e131.PubMedPubMedCentralCrossRef
70.
Lu C, Yang D, Klement JD, Oh IK, Savage NM, Waller JL, Colby AH, Grinstaff MW, Oberlies NH, Pearce CJ, et al. SUV39H1 represses the expression of cytotoxic T-Lymphocyte effector genes to promote colon tumor immune evasion. Cancer Immunol Res. 2019;7:414–27.PubMedPubMedCentralCrossRef
Metadata
Title
High copy number variations, particular transcription factors, and low immunity contribute to the stemness of prostate cancer cells
Authors
Zao Dai
Ping Liu
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-021-02870-x

Other articles of this Issue 1/2021

Journal of Translational Medicine 1/2021 Go to the issue

Review

Cellular and molecular mediators of lymphangiogenesis in inflammatory bowel disease

Research

Feasibility and utility of MRI and dynamic 18F-FDG-PET in an orthotopic organoid-based patient-derived mouse model of endometrial cancer

Correction

Correction to: The dysregulated innate immune response in severe COVID-19 pneumonia that could drive poorer outcome

Research

Model based on five tumour immune microenvironment-related genes for predicting hepatocellular carcinoma immunotherapy outcomes

Review

Avenues of research in dietary interventions to target tumor metabolism in osteosarcoma

Research

Identification of proteins associated with development of psoriatic arthritis in peripheral blood mononuclear cells: a quantitative iTRAQ-based proteomics study
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits