Colorectal neoplasia differentially expressed (CRNDE) is a novel gene that is activated early in colorectal cancer but whose regulation and functions are unknown. CRNDE transcripts are recognized as long non-coding RNAs (lncRNAs), which potentially interact with chromatin-modifying complexes to regulate gene expression via epigenetic changes. Complex alternative splicing results in numerous transcripts from this gene, and we have identified novel transcripts containing a highly-conserved sequence within intron 4 ("gVC-In4"). In colorectal cancer cells, we demonstrate that treatment with insulin and insulin-like growth factors (IGF) repressed CRNDE nuclear transcripts, including those encompassing gVC-In4. These repressive effects were negated by use of inhibitors against either the PI3K/Akt/mTOR pathway or Raf/MAPK pathway, suggesting CRNDE is a downstream target of both signaling cascades. Expression array analyses revealed that siRNA-mediated knockdown of gVC-In4 transcripts affected the expression of many genes, which showed correlation with insulin/IGF signaling pathway components and responses, including glucose and lipid metabolism. Some of the genes are identical to those affected by insulin treatment in the same cell line. The results suggest that CRNDE expression promotes the metabolic changes by which cancer cells switch to aerobic glycolysis (Warburg effect). This is the first report of a lncRNA regulated by insulin/IGFs, and our findings indicate a role for CRNDE nuclear transcripts in regulating cellular metabolism which may correlate with their upregulation in colorectal cancer.
Keywords: CRC; CRNDE; Colorectal cancer; Colorectal neoplasia differentially expressed; Genomic vertebrate conserved in intron 4; IGF1; IGF1R; IGF2; INSR; IPA; Ingenuity Pathway Analysis; Insulin; Insulin receptor; Insulin-like growth factor 1; Insulin-like growth factor 1 receptor; Insulin-like growth factor 2; Long non-coding RNA; MAPK; Mammalian target of rapamycin; Mitogen activated protein kinase; PI3K; Phosphatidylinositide 3-kinase; TCA; Tricarboxylic acid; Warburg effect; gVC-In4; lncRNA; mTOR.
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