Skip to main content

Advertisement

SpringerLink
Log in

Long noncoding RNA expression profile of infantile hemangioma identified by microarray analysis

  • Original Article
  • Published:
Tumor Biology

Abstract

Infantile hemangioma (IH) is one of the most common vascular tumors of childhood. Long noncoding RNAs (lncRNAs) play a critical role in angiogenesis, but their involvement in hemangioma remains unknown. This study aimed to assess the expression profiles of lncRNAs in IH and adjacent normal tissue samples, exploring the biological functions of lncRNAs as well as their involvement in IH pathogenesis. The lncRNA expression profiles were determined by lncRNA microarrays. A total of 1259 and 857 lncRNAs were upregulated and downregulated in IH, respectively, at a fold change cutoff of 2.0 (p < 0.05); in addition, 1469 and 1184 messenger RNAs (mRNAs) were upregulated and downregulated, respectively (fold change cutoff of 2.0; p < 0.05). A total of 292 differentially expressed mRNAs were targeted by the lncRNAs with altered expression in hemangioma, including 228 and 64 upregulated and downregulated, respectively (cutoff of 2.0, p < 0.05). Gene ontology (GO) analyses revealed several angiogenesis-related pathways. An lncRNA-mRNA co-expression network for differentially expressed lncRNAs revealed significant associations of the lncRNAs MEG3, MEG8, FENDRR, and Linc00152 with their related mRNAs. The validation results of nine differentially expressed lncRNAs (MALAT1, MEG3, MEG8, p29066, p33867, FENDRR, Linc00152, p44557_v4, p8683) as well as two mRNAs (FOXF1, EGFL7) indicated that the microarray data correlated well with the QPCR results. Interestingly, MALAT1 knockdown induced apoptosis and S-phase cell cycle arrest in human umbilical vein endothelial cells (HUVECs). Overall, this study revealed the lncRNA expression profile of IH and that lncRNAs likely regulate several genes with important roles in angiogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hoornweg MJ, Smeulders MJ, van der Horst CM. Prevalence and characteristics of haemangiomas in young children. Ned Tijdschr Geneeskd. 2005;149(44):2455–8.

    CAS  PubMed  Google Scholar 

  2. Kilcline C, Frieden IJ. Infantile hemangiomas: how common are they? A systematic review of the medical literature. Pediatr Dermatol. 2008;25(2):168–73. doi:10.1111/j.1525-1470.2008.00626.x.

    Article  PubMed  Google Scholar 

  3. Léauté-Labrèze C, Prey S, Ezzedine K. Infantile haemangioma: part I. Pathophysiology, epidemiology, clinical features, life cycle and associated structural abnormalities. J Eur Acad Dermatol Venereol. 2011;25(11):1245–53.

    Article  PubMed  Google Scholar 

  4. Chiller KG, Passaro D, Frieden IJ. Hemangiomas of infancy: clinical characteristics, morphologic subtypes, and their relationship to race, ethnicity, and sex. Arch Dermatol. 2002;138(12):1567–76.

    Article  PubMed  Google Scholar 

  5. Dickison P, Christou E, Wargon OA. Prospective study of infantile hemangiomas with a focus on incidence and risk factors. Pediatr Dermatol. 2011;28(6):663–9. doi:10.1111/j.1525-1470.2011.01568.x.

    Article  PubMed  Google Scholar 

  6. Bauland CG, Smit JM, Bartelink LR, Zondervan HA, Spauwen PH. Hemangioma in the newborn: increased incidence after chorionic villus sampling. Prenat Diagn. 2010;30(10):913–7. doi:10.1002/pd.2562.

    Article  PubMed  Google Scholar 

  7. Burton BK, Schulz CJ, Angle B, Burd LI. An increased incidence of haemangiomas in infants born following chorionic villus sampling (CVS. Prenat Diagn. 1995;15(3):209–14.

    Article  CAS  PubMed  Google Scholar 

  8. Haggstrom AN, Drolet BA, Baselga E, Chamlin SL, Garzon MC, Horii KA, et al. Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics. J Pediatr. 2007;150(3):291–4. doi:10.1016/j.jpeds.2006.12.003.

    Article  PubMed  Google Scholar 

  9. Selmin A, Foltran F, Chiarelli S, Ciullo R, Gregori D. An epidemiological study investigating the relationship between chorangioma and infantile hemangioma. Pathol Res Pract. 2014;210(9):548–53. doi:10.1016/j.prp.2014.04.007.

    Article  PubMed  Google Scholar 

  10. Munden A, Butschek R, Tom WL, Marshall JS, Poeltler DM, Krohne SE, et al. Prospective study of infantile haemangiomas: incidence, clinical characteristics and association with placental anomalies. Br J Dermatol. 2014;170(4):907–13. doi:10.1111/bjd.12804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Itinteang T, Withers AH, Davis PF, Tan ST. Biology of infantile hemangioma. Front Surg. 2014;1:38. doi:10.3389/fsurg.2014.00038.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Boscolo E, Bischoff J. Vasculogenesis in infantile hemangioma. Angiogenesis. 2009;12(2):197–207. doi:10.1007/s10456-009-9148-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huang L, Nakayama H, Klagsbrun M, Mulliken JB, Bischoff J. Glucose transporter 1-positive endothelial cells in infantile hemangioma exhibit features of facultative stem cells. Stem Cells. 2015;33(1):133–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu D, TM O, Shartava A, Fowles TC, Yang J, Fink LM, et al. Isolation, characterization, and in vitro propagation of infantile hemangioma stem cells and an in vivo mouse model. J Hematol Oncol. 2011;4:54. doi:10.1186/1756-8722-4-54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Greenberger S, Bischoff J. Pathogenesis of infantile haemangioma. Br J Dermatol. 2013;169(1):12–9. doi:10.1111/bjd.12435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Przewratil P, Sitkiewicz A, Andrzejewska E. Local serum levels of vascular endothelial growth factor in infantile hemangioma: intriguing mechanism of endothelial growth. Cytokine. 2010;49(2):141–7. doi:10.1016/j.cyto.2009.11.012.

    Article  CAS  PubMed  Google Scholar 

  17. Chen XD, Ma G, Huang JL, Chen H, Jin YB, Ye XX, et al. Serum-level changes of vascular endothelial growth factor in children with infantile hemangioma after oral propranolol therapy. Pediatr Dermatol. 2013;30(5):549–53. doi:10.1111/pde.12192.

    Article  PubMed  Google Scholar 

  18. Zou HX, Jia J, Zhang WF, Sun ZJ, Zhao YF. Propranolol inhibits endothelial progenitor cell homing: a possible treatment mechanism of infantile hemangioma. Cardiovasc Pathol. 2013;22(3):203–10. doi:10.1016/j.carpath.2012.10.001.

    Article  CAS  PubMed  Google Scholar 

  19. Jiang C, Lin X, Hu X, Chen H, Jin Y, Ma G, et al. Angiogenin: a potential serum marker of infantile hemangioma revealed by cDNA microarray analysis. Plast Reconstr Surg. 2014;134(2):231e–9e. doi:10.1097/prs.0000000000000367.

    Article  CAS  PubMed  Google Scholar 

  20. Stiles JM, Rowntree RK, Amaya C, Diaz D, Kokta V, Mitchell DC, et al. Gene expression analysis reveals marked differences in the transcriptome of infantile hemangioma endothelial cells compared to normal dermal microvascular endothelial cells. Vascular. Cell. 2013;5(1):6.

    CAS  Google Scholar 

  21. Calicchio M, Collins T. Hp. identification of signaling systems in proliferating and involuting phase infantile hemangiomas by genome-wide transcriptional profiling. Am J Pathol. 2009;174(5):1638–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Esteller M, Non-coding RNA. In human disease. Nat Rev Genet. 2011;12(12):861–74. doi:10.1038/nrg3074.

    Article  CAS  PubMed  Google Scholar 

  23. Michalik KM, You X, Manavski Y, Doddaballapur A, Zornig M, Braun T, et al. Long noncoding RNA MALAT1 regulates endothelial cell function and vessel growth. Circ Res. 2014;114(9):1389–97. doi:10.1161/CIRCRESAHA.114.303265.

    Article  CAS  PubMed  Google Scholar 

  24. Liu JY, Yao J, Li XM, Song YC, Wang XQ, Li YJ, et al. Pathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitus. Cell Death Dis. 2014;5:e1506. doi:10.1038/cddis.2014.466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Puthanveetil P, Chen S, Feng B, Gautam A, Chakrabarti S. Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells. J Cell Mol Med. 2015;19(6):1418–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gordon FE, Nutt CL, Cheunsuchon P, Nakayama Y, Provencher KA, Rice KA, et al. Increased expression of angiogenic genes in the brains of mouse meg3-null embryos. Endocrinology. 2010;151(6):2443–52. doi:10.1210/en.2009-1151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yuan SX, Yang F, Yang Y, Tao QF, Zhang J, Huang G, et al. Long noncoding RNA associated with microvascular invasion in hepatocellular carcinoma promotes angiogenesis and serves as a predictor for hepatocellular carcinoma patients’ poor recurrence-free survival after hepatectomy. Hepatology. 2012;56(6):2231–41. doi:10.1002/hep.25895.

    Article  CAS  PubMed  Google Scholar 

  28. Lu Z, Xiao Z, Liu F, Cui M, Li W, Yang Z et al. Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1). Oncotarget. 2015. doi:10.18632/oncotarget.6280.

  29. Jiang X, Yan Y, Hu M, Chen X, Wang Y, Dai Y, et al. Increased level of H19 long noncoding RNA promotes invasion, angiogenesis, and stemness of glioblastoma cells. J Neurosurg. 2015:1–8. doi:10.3171/2014.12.jns1426.

  30. Xie C, Mao X, Huang J, Ding Y, Wu J, Dong S, et al. KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases. Nucleic Acids Res. 2011;39(Web Server issue):W316–22. doi:10.1093/nar/gkr483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jia H, Osak M, Bogu GK, Stanton LW, Johnson R, Lipovich L. Genome-wide computational identification and manual annotation of human long noncoding RNA genes. RNA. 2010;16(8):1478–87. doi:10.1261/rna.1951310.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Takeuchi K, Yanai R, Kumase F, Morizane Y, Suzuki J, Kayama M, et al. EGF-like-domain-7 is required for VEGF-induced Akt/ERK activation and vascular tube formation in an ex vivo angiogenesis assay. PLoS One. 2014;9(3):e91849. doi:10.1371/journal.pone.0091849.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Gu T, He H, Han Z, Zeng T, Huang Z, Liu Q, et al. Expression of macro non-coding RNAs Meg8 and Irm in mouse embryonic development. Acta Histochem. 2012;114(4):392–9. doi:10.1016/j.acthis.2011.07.009.

    Article  CAS  PubMed  Google Scholar 

  34. Grote P, Wittler L, Hendrix D, Koch F, Wahrisch S, Beisaw A, et al. The tissue-specific lncRNA Fendrr is an essential regulator of heart and body wall development in the mouse. Dev Cell. 2013;24(2):206–14. doi:10.1016/j.devcel.2012.12.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ren X, Ustiyan V, Pradhan A, Cai Y, Havrilak JA, Bolte CS, et al. FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells. Circ Res. 2014;115(8):709–20. doi:10.1161/circresaha.115.304382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ji J, Tang J, Deng L, Xie Y, Jiang R, Li G et al. LINC00152 promotes proliferation in hepatocellular carcinoma by targeting EpCAM via the mTOR signaling pathway. Oncotarget. 2015. doi:10.18632/oncotarget.5970

  37. Zhou J, Zhi X, Wang L, Wang W, Li Z, Tang J, et al. Linc00152 promotes proliferation in gastric cancer through the EGFR-dependent pathway. J Exp Clin Cancer Res. 2015;34(1):135. doi:10.1186/s13046-015-0250-6.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Yang SL, Wu C, Xiong ZF, Fang X. Progress on hypoxia-inducible factor-3: its structure, gene regulation and biological function (review. Mol Med Rep. 2015;12(2):2411–6. doi:10.3892/mmr.2015.3689.

    CAS  PubMed  Google Scholar 

  39. Kanno T, Kamba T, Yamasaki T, Shibasaki N, Saito R, Terada N, et al. JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma. Oncogene. 2012;31(25):3098–110.

    Article  CAS  PubMed  Google Scholar 

  40. Shim M, Powers KL, Ewing SJ, Zhu S, Smart RC. Diminished expression of C/EBPα in skin carcinomas is linked to oncogenic Ras and reexpression of C/EBPα in carcinoma cells inhibits proliferation. Cancer Res. 2005;65(3):861–7.

    CAS  PubMed  Google Scholar 

  41. Al Hawas R, Ren Q, Ye S, Karim ZA, Filipovich AH, Whiteheart SW. Munc18b/STXBP2 is required for platelet secretion. Blood. 2012;120(12):2493–500. doi:10.1182/blood-2012-05-430629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jenjaroenpun P, Kremenska Y, Nair VM, Kremenskoy M, Joseph B, Kurochkin IV. Characterization of RNA in exosomes secreted by human breast cancer cell lines using next-generation sequencing. Peer J. 2013;1:e201. doi:10.7717/peerj.201.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wang L, LF W, Lu X, Mo XB, Tang ZX, Lei SF, et al. Integrated analyses of gene expression profiles digs out common markers for rheumatic diseases. PLoS One. 2015;10(9):e0137522. doi:10.1371/journal.pone.0137522.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Grote P, Herrmann BG. The long non-coding RNA Fendrr links epigenetic control mechanisms to gene regulatory networks in mammalian embryogenesis. RNA Biol. 2013;10(10):1579–85. doi:10.4161/rna.26165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sauvageau M, Goff LA, Lodato S, Bonev B, Groff AF, Gerhardinger C, et al. Multiple knockout mouse models reveal lincRNAs are required for life and brain development. Elife. 2013;2:e01749. doi:10.7554/eLife.01749.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Li L, Feng T, Lian Y, Zhang G, Garen A, Song X. Role of human noncoding RNAs in the control of tumorigenesis. Proc Natl Acad Sci. 2009;106(31):12956–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gutschner T, Hämmerle M, Eißmann M, Hsu J, Kim Y, Hung G, et al. The noncoding RNA MALAT1 is a critical regulator of the metastasis phenotype of lung cancer cells. Cancer Res. 2013;73(3):1180–9.

    Article  CAS  PubMed  Google Scholar 

  48. Yang L, Lin C, Liu W, Zhang J, Ohgi KA, Grinstein JD, et al. ncRNA-and Pc2 methylation-dependent gene relocation between nuclear structures mediates gene activation programs. Cell. 2011;147(4):773–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tripathi V, Shen Z, Chakraborty A, Giri S, Freier SM, Wu X, et al. Long noncoding RNA MALAT1 controls cell cycle progression by regulating the expression of oncogenic transcription factor B-MYB. PLoS Genet. 2013;9(3):e1003368. doi:10.1371/journal.pgen.1003368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Watts R, Ghozlan M, Hughey CC, Johnsen VL, Shearer J, Hittel DS. Myostatin inhibits proliferation and insulin-stimulated glucose uptake in mouse liver cells. Biochem Cell Biol. 2014;92(3):226–34. doi:10.1139/bcb-2014-0004.

    Article  CAS  PubMed  Google Scholar 

  51. Wang X, Li M, Wang Z, Han S, Tang X, Ge Y, et al. Silencing of long noncoding RNA MALAT1 by miR-101 and miR-217 inhibits proliferation, migration, and invasion of esophageal squamous cell carcinoma cells. J Biol Chem. 2015;290(7):3925–35. doi:10.1074/jbc.M114.596866.

    Article  CAS  PubMed  Google Scholar 

  52. Cheunsuchon P, Zhou Y, Zhang X, Lee H, Chen W, Nakayama Y, et al. Silencing of the imprinted DLK1-MEG3 locus in human clinically nonfunctioning pituitary adenomas. Am J Pathol. 2011;179(4):2120–30. doi:10.1016/j.ajpath.2011.07.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. De Cecco L, Negri T, Brich S, Mauro V, Bozzi F, Dagrada G, et al. Identification of a gene expression driven progression pathway in myxoid liposarcoma. Oncotarget. 2014;5(15):5965–77. doi:10.18632/oncotarget.2023.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Astorga J, Carlsson P. Hedgehog induction of murine vasculogenesis is mediated by Foxf1 and Bmp4. Development. 2007;134(20):3753–61. doi:10.1242/dev.004432.

    Article  CAS  PubMed  Google Scholar 

  55. Yan B, Yao J, Liu JY, Li XM, Wang XQ, Li YJ, et al. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circ Res. 2015;116(7):1143–56. doi:10.1161/CIRCRESAHA.116.305510.

    Article  CAS  PubMed  Google Scholar 

  56. Zhu Y, Zhang X, Qi L, Cai Y, Yang P, Xuan G, et al. HULC long noncoding RNA silencing suppresses angiogenesis by regulating ESM-1 via the PI3K/Akt/mTOR signaling pathway in human gliomas. Oncotarget. 2016;7(12):14429–40. doi:10.18632/oncotarget.7418.

    PubMed  PubMed Central  Google Scholar 

  57. Guo X, Yang Z, Zhi Q, Wang D, Guo L, Li G, et al. Long noncoding RNA OR3A4 promotes metastasis and tumorigenicity in gastric cancer. Oncotarget. 2016. doi:10.18632/oncotarget.7217.

    Google Scholar 

  58. WM F, YF L, BG H, Liang WC, Zhu X, Yang HD, et al. Long noncoding RNA Hotair mediated angiogenesis in nasopharyngeal carcinoma by direct and indirect signaling pathways. Oncotarget. 2016;7(4):4712–23. doi:10.18632/oncotarget.6731.

    Google Scholar 

  59. Schultz B, Yao X, Deng Y, Waner M, Spock C, Tom L, et al. A common polymorphism within the IGF2 imprinting control region is associated with parent of origin specific effects in infantile hemangiomas. PLoS One. 2015;10(10):e0113168. doi:10.1371/journal.pone.0113168.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Seo S, Singh HP, Lacal PM, Sasman A, Fatima A, Liu T, et al. Forkhead box transcription factor FoxC1 preserves corneal transparency by regulating vascular growth. Proc Natl Acad Sci. 2012;109(6):2015–20.

    Article  CAS  PubMed  Google Scholar 

  61. Amin DN, Bielenberg DR, Lifshits E, Heymach JV, Klagsbrun M, Targeting EGFR. Activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells. Microvasc Res. 2008;76(1):15–22.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant No. 81171828).

Author information

Authors and Affiliations

  1. Department of Burn & Plastic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong Province, China

    Xiaowen Liu, Renrong Lv, Linfeng Zhang, Guangqi Xu, Jianhai Bi, Feng Gao, Jian Zhang, Feng Xue, Fagang Wang, Yiliang Wu, Cong Fu & Ran Huo

  2. Department of Burn and Plastic Surgery, Tengzhou Central People’s Hospital, Tengzhou, Shandong Province, China

    Qiang Wang

Authors
  1. Xiaowen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Renrong Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Linfeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guangqi Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianhai Bi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Feng Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Feng Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fagang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yiliang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Cong Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Qiang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ran Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ran Huo.

Ethics declarations

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 81171828).

Conflicts of interest

None

Ethical approval

This study was approved by the ethics committee of Shandong Provincial Hospital, China (No. 2014-011).

Informed consent

Patient guardians provided verbal and written informed consent.

Electronic supplementary material

ESM 1

(DOCX 18 kb)

Supplementary Figure 1

Hierarchical clustering analysis of 2116 differentially expressed long noncoding RNAs (lncRNAs) and 2653 differentially expressed mRNAs. Red and green indicate increased and reduced expression levels, respectively. In the heat map, columns represent samples and rows are the various genes. Scale of expression level is shown on the horizontal bar. (GIF 352 kb)

High resolution image (TIFF 5128 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Lv, R., Zhang, L. et al. Long noncoding RNA expression profile of infantile hemangioma identified by microarray analysis. Tumor Biol. 37, 15977–15987 (2016). https://doi.org/10.1007/s13277-016-5434-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5434-y

Keywords

Search

Navigation