Advertisement

Functional evaluation of alternative splicing in the FAM190A gene

  • Sung Ung Kang
  • Joon Tae Park
Research Article
  • 31 Downloads

Abstract

The human FAM190A gene undergoes frequent alteration in human cancer, most commonly involving in-frame deletions in exon 9 or exons 9 & 10. These deletions form novel peptide sequences, serving as presumptive cancer-specific neo antigens. However, it remains elusive whether these in-frame deletions of FAM190A could induce oncogenic properties in vivo. In this study, we aimed to explore the functional significance of in-frame deletions in FAM190A genes. We generated two deletion mutant forms, FAM190AΔexon9 and FAM190AΔexon9&10, and examined their gain-of-function effects in vitro and in vivo. Global transcript profiling in NIH3T3 cells revealed that the transcripts displaying altered expression following introduction of FAM190AΔexon9 and FAM190AΔexon9&10 were significantly enriched for genes assigned to cellular movement and cell-to-cell signaling, respectively. Furthermore, ectopic expression of FAM190AΔexon9 and FAM190AΔexon9&10 induced in vivo tumor formation in nu/nu mice. Taken together, our results are the first to demonstrate the in vivo oncogenic properties of in-frame deletions in the FAM190A gene and indicate that these transcript variants might be clinically applicable as therapeutic targets in patients with cancer.

Keywords

FAM190A Alternative splicing Gain-of-function Neo antigens Xenograft 

Notes

Acknowledgements

This work was supported by an Incheon National University research Grant (2018-0240).

Compliance with ethical standards

Conflict of interest

Sung Ung Kang and Joon Tae Park declare that they have no conflict of interest.

Ethical approval

This study had been approved by the International Animal Care and Use Committee of Johns Hopkins Medicine (JHM) (protocol number: 20130112001).

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

13258_2018_752_MOESM1_ESM.pdf (119 kb)
Supplementary material 1 (PDF 118 KB)
13258_2018_752_MOESM2_ESM.pdf (76 kb)
Supplementary material 2 (PDF 76 KB)
13258_2018_752_MOESM3_ESM.pdf (85 kb)
Supplementary material 3 (PDF 84 KB)

References

  1. Bemmo A, Dias C, Rose AAN, Russo C, Siegel P, Majewski J (2010) Exon-level transcriptome profiling in murine breast cancer reveals splicing changes specific to tumors with different metastatic abilities. PLoS ONE 5:e11981CrossRefGoogle Scholar
  2. Bonomi S, Gallo S, Catillo M, Pignataro D, Biamonti G, Ghigna C (2013) Oncogenic alternative splicing switches: role in cancer progression and prospects for therapy. Int J Cell Biol 2013:17CrossRefGoogle Scholar
  3. Caceres JF, Kornblihtt AR (2002) Alternative splicing: multiple control mechanisms and involvement in human disease. Trends Genet 18:186–193CrossRefGoogle Scholar
  4. Danckwardt S, Neu-Yilik G, Thermann R, Frede U, Hentze MW, Kulozik AE (2002) Abnormally spliced β-globin mRNAs: a single point mutation generates transcripts sensitive and insensitive to nonsense-mediated mRNA decay. Blood 99:1811–1816CrossRefGoogle Scholar
  5. Dang L, Fan X, Chaudhry A, Wang M, Gaiano N, Eberhart CG (2006) Notch3 signaling initiates choroid plexus tumor formation. Oncogene 25:487–491CrossRefGoogle Scholar
  6. DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T (2012) Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482:405–409CrossRefGoogle Scholar
  7. Fackenthal JD, Godley LA (2008) Aberrant RNA splicing and its functional consequences in cancer cells. Dis Models Mech 1:37–42CrossRefGoogle Scholar
  8. Fungtammasan A, Walsh E, Chiaromonte F, Eckert KA, Makova KD (2012) A genome-wide analysis of common fragile sites: what features determine chromosomal instability in the human genome? Genome Res 22:993–1005CrossRefGoogle Scholar
  9. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, Ivanova Y, Hundal J, Arthur CD, Krebber WJ et al (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:577–581CrossRefGoogle Scholar
  10. He C, Zhou F, Zuo Z, Cheng H, Zhou R (2009) A global view of cancer-specific transcript variants by subtractive transcriptome-wide analysis. PLoS ONE 4:e4732CrossRefGoogle Scholar
  11. Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361:1475–1485CrossRefGoogle Scholar
  12. Maniatis T, Tasic B (2002) Alternative pre-mRNA splicing and proteome expansion in metazoans. Nature 418:236–243CrossRefGoogle Scholar
  13. Matlin AJ, Clark F, Smith CWJ (2005) Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 6:386–398CrossRefGoogle Scholar
  14. Patel K, Scrimieri F, Ghosh S, Zhong J, Kim M-S, Ren YR, Morgan RA, Iacobuzio-Donahue CA, Pandey A, Kern SE (2013) FAM190A deficiency creates a cell division defect. Am J Pathol 183:296–303CrossRefGoogle Scholar
  15. Provost E, Rhee J, Leach SD (2007) Viral 2A peptides allow expression of multiple proteins from a single ORF in transgenic zebrafish embryos. Genesis 45:625–629CrossRefGoogle Scholar
  16. Sak K (2012) Chemotherapy and dietary phytochemical agents. Chemother Res Pract 2012:282570PubMedPubMedCentralGoogle Scholar
  17. Scrimieri F, Calhoun ES, Patel K, Gupta R, Huso DL, Hruban RH, Kern SE (2011) FAM190A rearrangements provide a multitude of individualized tumor signatures and neo-antigens in cancer. Oncotarget 2:69–75CrossRefGoogle Scholar
  18. Skotheim RI, Nees M (2007) Alternative splicing in cancer: noise, functional, or systematic? Int J Biochem Cell Biol 39:1432–1449CrossRefGoogle Scholar
  19. Venables JP (2004) Aberrant and alternative splicing in cancer. Can Res 64:7647–7654CrossRefGoogle Scholar
  20. Wang R-F, Wang HY (2017) Immune targets and neoantigens for cancer immunotherapy and precision medicine. Cell Res 27:11–37CrossRefGoogle Scholar
  21. Yaari G, Bolen CR, Thakar J, Kleinstein SH (2013) Quantitative set analysis for gene expression: a method to quantify gene set differential expression including gene-gene correlations. Nucleic Acids Res 41:e170–e170CrossRefGoogle Scholar

Copyright information

© The Genetics Society of Korea and Springer Nature B.V. 2018

Authors and Affiliations

  1. 1.Institute of Cell EngineeringJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Division of Life Sciences, College of Life Sciences and BioengineeringIncheon National UniversityIncheonSouth Korea

Personalised recommendations