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

• Published in: Biochemical and biophysical research communications Vol. 440; no. 1; pp. 99 - 104
• Main Authors: Franklin, Jeffrey L., Rankin, Carl R., Levy, Shawn, Snoddy, Jay R., Zhang, Bing, Washington, Mary Kay, Thomson, J. Michael, Whitehead, Robert H., Coffey, Robert J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-10-2013
• Subjects: 60 APPLIED LIFE SCIENCES; AGAR; Animals; Cell Transformation, Neoplastic; Colon; Colon - metabolism; Colon - pathology; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HOMEOSTASIS; IN-SITU HYBRIDIZATION; Intestine; LARGE INTESTINE; LET; let-7; METASTASES; MICE; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; NEOPLASMS; Non-coding RNA; NUCLEAR REACTION ANALYSIS; POLYMERASE CHAIN REACTION; Progenitor cells; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; lncRNAs; let-7; UTRs; Colorectal cancer; ncNRFR; aRNA; GSEA; siRNA; Progenitor cells; PCC; Intestine; dpc; YAMC; Colon; Non-coding RNA; PCR; BrdU; ISH; non-coding Nras functional RNA; progenitor cell compartment; polymerase chain reaction; Young adult mouse colon; small interfering RNAs; untranslated regions; days postcoitus; bromodeoxyuridine; gene set enrichment analysis; amplified RNA; long non-coding RNAs; in situ hybridization
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2013.09.040

•Non-coding RNAs are found in the colonic crypt progenitor compartment.•Colonocytes transformed by ncNRFR are highly invasive and metastatic.•ncNRFR has a region similar to the miRNA, let-7 family.•ncNRFR expression alters let-7 activity as measured by reporter construct.•ncNRFR expression upregulates let-7b targets.
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.