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

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.

Transposable elements drive widespread expression of oncogenes in human cancers

“…1b). A comprehensive list of 702 oncogenes was generated from previously annotated onco-exaptation examples 4,15 and ONGene 19 (Supplementary Table 1). Considering the technical limitations of RNA-seq data, we set stringent filters (Methods) to maximize the specificity for onco-exaptation events.…”

IL‑33 notably inhibits the growth of colon cancer cells

“…In the present study, no mRNA or protein expression levels of IL-33 in HCT-116 cells were investigated due to it being demonstrated that IL-33 is undetectable in the HCT-116 colon cancer cell line ( 23 ). If IL-33 was determined to be highly expressed in this cancer cell line, then it may be necessary to knock out or block endogenous IL-33 to further confirm the initial data.…”

“…If IL-33 was determined to be highly expressed in this cancer cell line, then it may be necessary to knock out or block endogenous IL-33 to further confirm the initial data. Although IL-33 is not detectable in HCT-116 colon cancer cells ( 23 ), numerous other types of cells, including activated immune cells, fibroblasts and endothelial cells have been reported to produce IL-33 ( 24 ). Thus, it is possible that IL-33 produced by these cells may have an effect on the pathogenesis of colon cancer in a biological setting ( 24 ).…”

High-Throughput Sequencing is a Crucial Tool to Investigate the Contribution of Human Endogenous Retroviruses (HERVs) to Human Biology and Development

“…HERVs are known to be de-silenced, and hence, transcriptionally activated in cancer. Accordingly, HERV transcriptional activity has been found to be significantly upregulated in cancer cells than in controls [ 73 , 80 , 86 , 109 , 110 , 111 ].…”