A new study provides evidence that noncoding RNAs and interactions between noncoding genes play a much greater role in human cancer than was previously understood. The research, published by Cell Press in the September issue of the journal Cancer Cell, may be useful for identifying tumor-specific signatures associated with diagnosis, prognosis, and treatment of cancer.
Malignant cells exhibit genetic alterations in oncogenes or tumor suppressor genes. More recently, a large class of noncoding RNA transcripts called microRNAs (miRNAs) has also been included in the genetic signature of cancer. MicroRNAs are small RNAs that can regulate gene expression by inhibiting protein translation, and recent research has implicated miRNAs in cancer initiation and progression.
Dr. Carlo M. Croce from Ohio State University, Dr. Massimo Negrini from the University of Ferrara, Italy, and colleagues investigated the role of additional classes of highly conserved noncoding RNAs in human cancer that have not been studied to the extent of miRNAs. "This research will offer new insights into the molecular mechanisms and signal transduction pathways altered in cancer and may present opportunities for the identification of new molecular markers and potential therapeutic agents," explains Dr. Croce.
Using genome-wide profiling in a large panel of normal and cancer samples, the researchers discovered that genomic ultraconserved regions (UCRs) encode a particular set of noncoding RNAs whose expression is altered in human leukemias and carcinomas. These UCRs are highly conserved among different species, and although they do not encode proteins, they are likely to be functional. Inhibition of an overexpressed UCR induced apoptosis in colon cancer cells. Interestingly, the researchers also identified a functional role of miRNAs in the transcriptional regulation of UCRs associated with cancer.
Taken together with the current knowledge of miRNAs, these results provide strong support for a model that considers alteration of both coding and noncoding RNAs in the initiation and progression of human cancer. "We found that noncoding UCRs are consistently altered at the genomic level in a high percentage of leukemias and carcinomas and may interact with miRNAs. The findings provide support for a model in which both coding and noncoding genes are involved in and cooperate in human tumorigenesis," concludes Dr. Croce. Further research is needed to investigate the complex functional interactions between multiple types of noncoding RNAs.
The researchers include George A. Calin and Chang-gong Liu of The Ohio State University in Columbus; Manuela Ferracin of University of Ferrara in Ferrara; Terry Hyslop of Thomas Jefferson University in Philadelphia; Riccardo Spizzo of The Ohio State University in Columbus; Cinzia Sevignani of Thomas Jefferson University in Philadelphia; Muller Fabbri, Amelia Cimmino, Eun Joo Lee, Sylwia E. Wojcik, Masayoshi Shimizu, and Esmerina Tili of The Ohio State University in Columbus; Simona Rossi of University of Ferrara in Ferrara; Cristian Taccioli, Flavia Pichiorri, Xiuping Liu, of The Ohio State University in Columbus; Simona Zupo of Advanced Biotechnology Center in Genoa; Vlad Herlea of University Clinical Fundeni Hospital in Bucharest; Laura Gramantieri of University of Bologna in Bologna; Giovanni Lanza of University of Ferrara in Ferrara; Hansjuerg Alder of The Ohio State University in Columbus; Laura Rassenti of University of California in San Diego; Stefano Volinia, of The Ohio State University in Columbus and University of Ferrara in Ferrara; Thomas D. Schmittgen of The Ohio State University in Columbus; Thomas J. Kipps of University of California in San Diego; Massimo Negrini of The Ohio State University in Columbus and University of Ferrara in Ferrara; and Carlo M. Croce of The Ohio State University in Columbus
This work was supported by National Cancer Institute grants to C.M.C., T.J.K., and T.D.S.; by a Sydney Kimmel Research Foundation award and by a CLL Global Research Foundation grant to G.A.C.; by grants from the Italian Ministry of Public Health, the Italian Ministry of University Research, and the Italian Association for Cancer Research (AIRC) to M.N., L.G., G.L., and S.V.; by Comitato dei Sostenitori to M.N.; and by a FIRB grant to S.Z. and M.N. M.F. is a recipient of a fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC).
Calin et al.: "Ultraconserved Regions Encoding ncRNAs Are Altered in Human Leukemias and Carcinomas." Publishing in Cancer Cell 12, 215-229, September 2007. DOI 10.1016/j.ccr.2007.07.027 http://www.