A novel isoform of IL-33 revealed by screening for transposable element promoted genes in human colorectal cancer

PLoS One. 2017 Jul 17;12(7):e0180659. doi: 10.1371/journal.pone.0180659. eCollection 2017.

Abstract

Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences contain multiple regulatory motifs and hence are capable of influencing expression of host genes. TEs are known to be released from epigenetic repression and can become transcriptionally active in cancer. Such activation could also lead to lineage-inappropriate activation of oncogenes, as previously described in lymphomas. However, there are few reports of this mechanism occurring in non-blood cancers. Here, we re-analyzed whole transcriptome data from a large cohort of patients with colon cancer, compared to matched normal colon control samples, to detect genes or transcripts ectopically expressed through activation of TE promoters. Among many such transcripts, we identified six where the affected gene has described role in cancer and where the TE-driven gene mRNA is expressed in primary colon cancer, but not normal matched tissue, and confirmed expression in colon cancer-derived cell lines. We further characterized a TE-gene chimeric transcript involving the Interleukin 33 (IL-33) gene (termed LTR-IL-33), that is ectopically expressed in a subset of colon cancer samples through the use of an endogenous retroviral long terminal repeat (LTR) promoter of the MSTD family. The LTR-IL-33 chimeric transcript encodes a novel shorter isoform of the protein, which is missing the initial N-terminus (including many conserved residues) of Native IL-33. In vitro studies showed that LTR-IL-33 expression is required for optimal CRC cell line growth as 3D colonospheres. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in colon cancer.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms / pathology*
  • DNA Transposable Elements / genetics*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-33 / chemistry
  • Interleukin-33 / genetics*
  • Promoter Regions, Genetic / genetics
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Terminal Repeat Sequences / genetics

Substances

  • DNA Transposable Elements
  • IL33 protein, human
  • Interleukin-33
  • Protein Isoforms

Grants and funding

This research was supported by a grant to DLM from the Canadian Cancer Society Research Institute: http://www.cancer.ca/research. AB is supported by an Alexander Graham Bell Canada Graduate Scholarship from the Natural Sciences and Engineering Research Council of Canada: http://www.nserc-crsng.gc.ca/. MMK was partly supported by a postdoctoral fellowship from the Michael Smith Foundation for Health Research: http://www.msfhr.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.