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Address for correspondence: S. Patrick Nana-Sinkam, M.D., The Ohio State University Medical Center, Division of Pulmonary, Critical Care and Sleep Medicine, 201 Davis Heart & Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210. Phone: 614-247-7707. Fax: 614-293-4799
In the last decade, researchers have identified a novel mode of gene regulation in the form of a family of small RNAs. In 1993, investigators first identified in C. elegans a small RNA, lin-4, which affected developmental timing by forming a duplex with the 3′UTR of another gene, lin-14, thus preventing lin-14 translation.
The identification of lin-4 represented the first small RNA-regulating target mRNA expression. In 2000, investigators identified another small RNA let-7 that regulated the gene let-4; however, unlike lin-4, let-7 was conserved across among several species.
Since this initial discovery, many small RNAs have been identified as potential regulators of gene expression and have been termed microRNAs (miRNAs, mirs). MiRNAs are a family of small noncoding RNAs (approximately 21–25 nucleotides (nt) long) expressed in many organisms, including animals, plants, and viruses. MiRNAs originate from stem-loop precursors and are candidates for the regulation of both translation and mRNA degradation by base pairing to complementary sites of target mRNA.
The biological functions and mechanisms by which miRNAs are regulated remain poorly understood. A single miRNA may bind to and regulate several target mRNAs, whereas several miRNAs may bind and regulate the same target mRNA.
Data suggest that miRNAs seem to be integral to several biological functions, including gene regulation, apoptosis, hematopoetic development, and maintenance of cell differentiation. MiRNAs have been identified in several human neurodegenerative metabolic diseases and malignancies.
As illustrated in Figure 1, within the nucleus, miRNAs are transcribed as long primary transcripts by RNA polymerase II into primary miRNAs (pri-miRNAs), which range from hundreds to thousands of nucleotides in length.
While in the nucleus, Drosha, an RNase III, in conjunction with either DiGeorge syndrome (critical region gene 8 [DGCR8] in humans) or Pasha (double-stranded RNA binding domain dsRBD protein in Drosophila and C. elegans), cleaves both strands of the pri-miRNA to release a 70- to 100-nucleotide stem loop, termed the precursor miRNA (pre-miRNA).
Once in the cytoplasm, a second RNase III termed Dicer, in conjunction with a dsRBD, cleaves the pre-miRNA, releasing an approximately 22-nucleotide RNA duplex (mature miRNA and its complement miRNA*).
Researchers first identified a link between miRNA expression and human malignancy with the observation that there was a downregulation or deletion of miRNAs mir-15-a and mir-16-1 in locus 13q14 in patients with B-cell chronic lymphocytic leukemia (CLL).
Since that discovery, researchers have identified abnormal expression of miRNAs in several types of malignancies, including CLL, colorectal neoplasia, Burkettt's lymphoma, large-cell lymphoma, breast cancer, lung cancer, and hepatocellular and thyroid carcinoma.
first identified a connection between miRNA expression and genes relevant to lung cancer. The investigators observed an inverse relationship between let-7 and RAS protein expression in human cancer cell lines. Furthermore, microarray analysis of human cancerous tissue demonstrated decreased let-7 expression in lung cancer but not in adjacent normal lung tissue, colon cancer, or breast cancer.
used microarray analysis to identify distinct miRNA profiles between lung cancer and noncancerous tissue. In addition, the investigators identified five distinct miRNAs that predicted prognosis among patients with adenocarcinoma.
MiRNAs are a novel family of small RNAs that are integral to several biological functions and that regulate gene expression in many human diseases, including malignancies. The identification of this new layer of gene regulation and the potential targets may prove important in diagnosis, treatment, and prognosis in lung cancers.