Malignant transformation of colonic epithelial cells by a colon-derived long noncoding RNA

Abstract

Recent progress has been made in the identification of protein-coding genes and miRNAs that are expressed in and alter the behavior of colonic epithelia. However, the role of long non-coding RNAs (lncRNAs) in colonic homeostasis is just beginning to be explored. By gene expression profiling of post-mitotic, differentiated tops and proliferative, progenitor-compartment bottoms of microdissected adult mouse colonic crypts, we identified several lncRNAs more highly expressed in crypt bottoms. One identified lncRNA, designated non-coding Nras functional RNA (ncNRFR), resides within the Nras locus but appears to be independent of the Nras coding transcript. Stable overexpression of ncNRFR in non-transformed, conditionally immortalized mouse colonocytes results in malignant transformation, as determined by growth in soft agar and formation of highly invasive tumors in nude mice. Moreover, ncNRFR appears to inhibit the function of the tumor suppressor let-7. These results suggest precise regulation of ncNRFR is necessary for proper cell growth in the colonic crypt, and its misregulation results in neoplastic transformation.

Keywords: BrdU; Colon; Colorectal cancer; GSEA; ISH; Intestine; Non-coding RNA; PCC; PCR; Progenitor cells; UTRs; YAMC; Young adult mouse colon; aRNA; amplified RNA; bromodeoxyuridine; days postcoitus; dpc; gene set enrichment analysis; in situ hybridization; let-7; lncRNAs; long non-coding RNAs; ncNRFR; non-coding Nras functional RNA; polymerase chain reaction; progenitor cell compartment; siRNA; small interfering RNAs; untranslated regions.