Top

World Journal of Surgical Oncology

Published in:

Open Access 01-12-2017 | Research

Integrated network analysis to explore the key genes regulated by parathyroid hormone receptor 1 in osteosarcoma

Authors: Donghui Guan, Honglai Tian

Published in: World Journal of Surgical Oncology | Issue 1/2017

Abstract

Background

As an invasive malignant tumor, osteosarcoma (OS) has high mortality. Parathyroid hormone receptor 1 (PTHR1) contributes to maintaining proliferation and undifferentiated state of OS. This study is designed to reveal the action mechanisms of PTHR1 in OS.

Methods

Microarray dataset GSE46861, which included six PTHR1 knockdown OS samples and six control OS samples, was obtained from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified and then performed with enrichment analysis separately using the limma package and DAVID online tool. Then, protein-protein interaction (PPI) network and module analyses were conducted using Cytoscape software. Using the WebGestalt tool, microRNAs (miRNAs) were predicted for the DEGs involved in the PPI network. Following this, transcription factors (TFs) were predicted and an integrated network was constructed by Cytoscape software.

Results

There were 871 DEGs in the PTHR1 knockdown OS samples compared with the control OS samples. Besides, upregulated ZFPM2 was involved in the miRNA-DEG regulatory network. Moreover, TF LEF1 was predicted for the miRNA-DEG regulatory network of the downregulated genes. In addition, LEF1, NR4A2, HAS2, and RHOC had higher degrees in the integrated network.

Conclusions

ZFPM2, LEF1, NR4A2, HAS2, and RHOC might be potential targets of PTHR1 in OS.

Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment—where do we stand? A state of the art review. Cancer Treat Rev. 2014;40:523–32.CrossRefPubMed

Ottaviani G, Jaffe N, Eftekhari F, Raymond AK, Yasko AW. Pediatric and adolescent osteosarcoma. Berlin: Springer; 2011.

Mohseny AB, Tieken C, van der Velden PA, Szuhai K, de Andrea C, Hogendoorn PC, Cleton-Jansen AM. Small deletions but not methylation underlie CDKN2A/p16 loss of expression in conventional osteosarcoma. Genes Chromosomes Cancer. 2010;49:1095–103.CrossRefPubMed

Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3–13.CrossRefPubMed

Wang F, Ke ZF, Sun SJ, Chen WF, Yang SC, Li SH, Mao XP, Wang L. Oncogenic roles of astrocyte elevated gene-1 (AEG-1) in osteosarcoma progression and prognosis. Cancer Biol Ther. 2011;12:539–48.CrossRefPubMed

Wang F, Ke ZF, Wang R, Wang YF, Huang LL, Wang LT. Astrocyte elevated gene-1 (AEG-1) promotes osteosarcoma cell invasion through the JNK/c-Jun/MMP-2 pathway. Biochem Biophys Res Commun. 2014;452:933–9.CrossRefPubMed

Yang D, Liu G, Wang K. miR-203 acts as a tumor suppressor gene in osteosarcoma by regulating RAB22A. PLoS One. 2015;10:e0132225.CrossRefPubMedPubMedCentral

Mei L, Ye Z, Zhang H, Li L, Peng H, Hong X, Yu Z, Mao C. Delivery of inhibitor of growth 4 (ING4) gene significantly inhibits proliferation and invasion and promotes apoptosis of human osteosarcoma cells. Sci Rep. 2014;4:7380.

Xu M, Xie Y, Sheng W, Miao J, Yang J. Adenovirus-mediated ING4 gene transfer in osteosarcoma suppresses tumor growth via induction of apoptosis and inhibition of tumor angiogenesis. Technol Cancer Res Treat. 2015;14:617–26.CrossRefPubMed

10.

Liu Z, Zhang Y, Li Y, Liu B, Zhang K. miR-24 represses metastasis of human osteosarcoma cells by targeting Ack1 via AKT/MMPs pathway. Biochem Biophys Res Commun. 2017;486:211–7.CrossRefPubMed

11.

Ho PW, Goradia A, Russell MR, Chalk AM, Milley KM, Baker EK, Danks JA, Slavin JL, Walia M, Crimeenirwin B. Knockdown of PTHR1 in osteosarcoma cells decreases invasion and growth and increases tumor differentiation in vivo. Oncogene. 2014;34:2922–33.CrossRefPubMed

12.

Ho PW, Russell M, Goradia A, Chalk A, Slavin J, Dickins R, Martin TJ, Walkley C. Abstract A54: PTHR1 signaling regulates the invasion and differentiation stage of osteosarcoma. Cancer Res. 2014;74:A54.CrossRef

13.

Yang R, Hoang BH, Kubo T, Kawano H, Chou A, Sowers R, Huvos AG, Meyers PA, Healey JH, Gorlick R. Over-expression of parathyroid hormone Type 1 receptor confers an aggressive phenotype in osteosarcoma. Int J Cancer. 2007;121:943–54.CrossRefPubMed

14.

Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4:249–64.CrossRefPubMed

15.

Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47–e47.CrossRefPubMedPubMedCentral

16.

Consortium TGO. Gene Ontology Consortium: going forward. Nucleic Acids Res. 2015;43:1049–56.CrossRef

17.

Kanehisa M, Sato Y, Kawashima M, Furumichi M, Tanabe M. KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 2015;44:D457–D62.CrossRefPubMedPubMedCentral

18.

Huang DW. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 2007;35:W169.CrossRefPubMedPubMedCentral

19.

Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, Lin J, Minguez P, Bork P, von Mering C. STRING v9. 1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 2013;41:D808–D15.CrossRefPubMed

20.

Saito R, Smoot ME, Ono K, Ruscheinski J, Wang P-L, Lotia S, Pico AR, Bader GD, Ideker T. A travel guide to Cytoscape plugins. Nat Methods. 2012;9:1069–76.CrossRefPubMedPubMedCentral

21.

Tang Y, Li M, Wang J, Pan Y, Wu FX. CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Bio Systems. 2015;127:67–72.CrossRefPubMed

22.

He X, Zhang J. Why do hubs tend to be essential in protein networks? PLoS Genet. 2006;2:826–34.CrossRef

23.

Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics. 2003;4:1–27.CrossRef

24.

Wang J, Duncan D, Shi Z, Zhang B. WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013. Nucleic Acids Res. 2013;41:77–83.CrossRef

25.

Janky RS, Verfaillie A, Imrichová H, Sande BVD, Standaert L, Christiaens V, Hulselmans G, Herten K, Sanchez MN, Potier D. iRegulon: from a gene list to a gene regulatory network using large motif and track collections. PLoS Comput Biol. 2014;10:e1003731.CrossRefPubMedPubMedCentral

26.

Fatemeh M, Maryam HGK, Taghi GM, Taghi L. Spontaneous expression of neurotrophic factors and TH, Nurr1, Nestin genes in long-term culture of bone marrow mesenchymal stem cells. Cell J. 2012;13:243.

27.

Maijenburg MW, Gilissen C, Melief SM, Kleijer M, Weijer K, Ten BA, Roelofs H, Van Tiel CM, Veltman JA, de Vries CJ. Nuclear receptors Nur77 and Nurr1 modulate mesenchymal stromal cell migration. Stem Cells Dev. 2012;21:228–38.CrossRefPubMed

28.

Nervina JM, Magyar CE, Pirih FQ, Tetradis S. PGC-1alpha is induced by parathyroid hormone and coactivates Nurr1-mediated promoter activity in osteoblasts. Bone. 2006;39:1018–25.CrossRefPubMed

29.

Siyahian AJ. PTH and Nurr1 mediated gene expression in osteoblasts. Dissertations & Theses - Gradworks. Los Angeles: University of California; 2009.

30.

Mix KS, Attur MG, Al-Mussawir H, Abramson SB, Brinckerhoff CE, Murphy EP. Transcriptional repression of matrix metalloproteinase gene expression by the orphan nuclear receptor NURR1 in cartilage. J Biol Chem. 2007;282:9492–504.CrossRefPubMed

31.

Nishida Y, Knudson W, Knudson CB, Ishiguro N. Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity. Exp Cell Res. 2005;307:194–203.CrossRefPubMedPubMedCentral

32.

Nikitovic D, Zafiropoulos A, Katonis P, Tsatsakis A, Theocharis AD, Karamanos NK, Tzanakakis GN. Transforming growth factor-beta as a key molecule triggering the expression of versican isoforms v0 and v1, hyaluronan synthase-2 and synthesis of hyaluronan in malignant osteosarcoma cells. IUBMB Life. 2006;58:47–53.CrossRefPubMed

33.

Falconi D, Aubin JE. LIF inhibits osteoblast differentiation at least in part by regulation of HAS2 and its product hyaluronan. J Bone Miner Res. 2007;22:1289–300.CrossRefPubMed

34.

Du HZ, Liu XM, Zhang YX. Expression of RhoC and MMP-9 in osteosarcoma and its clinicopathological significance. Mod Prev Med. 2010;37:1794–7.

35.

Tang CY, Jiang-Dong NI. Molecular mechanisms of RhoC inducing invasion and metastasis of osteosarcoma. J Clin Res. 2007;24:1639–43.

36.

Huang J, Peng J, Cao G, Lu S, Liu L, Li Z, Zhou M, Feng M, Shen H. Hypoxia-induced MicroRNA-429 promotes differentiation of MC3T3-E1 osteoblastic cells by mediating ZFPM2 expression. Cell Physiol Biochem. 2016;39:1177–86.CrossRefPubMed

37.

Kahler RA, Galindo M, Lian J, Stein GS, van Wijnen AJ, Westendorf JJ. Lymphocyte enhancer-binding factor 1 (Lef1) inhibits terminal differentiation of osteoblasts. J Cell Biochem. 2006;97:969–83.CrossRefPubMed

38.

Kahler RA, Yingst SM, Hoeppner LH, Jensen ED, Krawczak D, Oxford JT, Westendorf JJ. Collagen 11a1 is indirectly activated by lymphocyte enhancer-binding factor 1 (Lef1) and negatively regulates osteoblast maturation. Matrix Biol. 2008;27:330–8.CrossRefPubMedPubMedCentral

39.

Huang FI, Chen YL, Chang CN, Yuan RH, Jeng YM. Hepatocyte growth factor activates Wnt pathway by transcriptional activation of LEF1 to facilitate tumor invasion. Carcinogenesis. 2012;33:1142–8.CrossRefPubMed

40.

Hoeppner LH, Secreto F, Jensen ED, Li X, Kahler RA, Westendorf JJ. Runx2 and bone morphogenic protein 2 regulate the expression of an alternative Lef1 transcript during osteoblast maturation. J Cell Physiol. 2009;221:480–9.CrossRefPubMed

41.

Galindo M, Kahler RA, Teplyuk NM, Stein JL, Lian JB, Stein GS, Westendorf JJ, van Wijnen AJ. Cell cycle related modulations in Runx2 protein levels are independent of lymphocyte enhancer-binding factor 1 (Lef1) in proliferating osteoblasts. J Mol Histol. 2007;38:501–6.CrossRefPubMed

Title: Integrated network analysis to explore the key genes regulated by parathyroid hormone receptor 1 in osteosarcoma
Authors: Donghui Guan
Honglai Tian
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: World Journal of Surgical Oncology / Issue 1/2017
Electronic ISSN: 1477-7819
DOI: https://doi.org/10.1186/s12957-017-1242-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Integrated network analysis to explore the key genes regulated by parathyroid hormone receptor 1 in osteosarcoma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

The significance of a nineteenth century definition in the era of genomics: linitis plastica

Erratum to: Cytotoxic effect of different treatment parameters in pressurized intraperitoneal aerosol chemotherapy (PIPAC) on the in vitro proliferation of human colonic cancer cells

The effects of chemoradiotherapy on recurrence and survival in locally advanced rectal cancers with curative total mesorectal excision: a prospective, nonrandomized study

Epidemiological characteristics of primary spinal osseous tumors in Eastern China

Positive surgical margin following radical nephrectomy is an independent predictor of local recurrence and disease-specific survival

Focal necrosis mimicking breast cancer following coronary bypass grafting