In the last decade, a new class of oncogenic factors has emerged. Noncoding RNAs (RNAs that do not encode proteins), especially micro-RNAs (miRNAs), play a critical role in tumorigenesis. Generation of miRNAs typically involves the transcription of a precursor RNA that, through a number of processing steps, is trimmed down to a 20–22-nucleotide-long mature miRNA. The mature miRNA usually base-pairs with the 3′ untranslated region (UTR) of its target RNA and inhibits its translation, or sometimes causes its degradation. To date, more than 1500 miRNAs have been identified in humans and have been implicated in the regulation of as many as 30 percent of the cell’s mRNAs, with fundamental roles in cell proliferation, differentiation, and apoptosis. A number of miRNAs have also been shown to function as tumor-suppressor genes or oncogenes.

The first known role for miRNAs in tumorigenesis was revealed by the analysis of chromosomal region 13q14.3. This genomic region is found deleted in most cases of chronic lymphocytic leukemia (CLL), prostate cancer, and pituitary adenomas. Characterization of the disease-causing deletion showed that the absence of two miRNAs, miR-15-a and miR-16-1, causes CLL. Mice with mutations in both miRNAs develop CLL. The two miRNAs appear to control cell proliferation genes. In their absence, proliferation of B cells is increased. Similarly, the let-7 family of miRNAs has been implicated in lung, colon, breast, and ovarian cancer. Let-7 miRNAs down-regulate the translation of Ras. Thus in the absence of the miRNAs, Ras is constitutively overproduced, contributing to tumorigenesis. Let-7 miRNAs have other targets as well, such as the oncogenic transcription factor MYC, which we will discuss in detail in the next section. A general theme that emerges in the study of miRNAs in cancer is that each miRNA has multiple targets, and therefore ample opportunities to contribute to tumorigenesis.

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Like proteins involved in tumorigenesis, miRNAs can function like tumor suppressors or oncogenes. The miRNAs miR-15-a and miR-16-1 act like tumor-suppressors; they normally inhibit cell proliferation, and their absence leads to cell growth. However, some miRNAs have also been found to be overexpressed in cancer, and their analysis indicates that they function like oncogenes. Of particular interest is miR-21, which is overexpressed in most solid tumors, including glioblastomas and breast, lung, pancreatic, and colon tumors. This miRNA targets several tumor-suppressor genes, among them the gene encoding the PTEN phosphatase. Much more needs to be learned about how miRNAs contribute to tumorigenesis, but it is clear that through their ability to regulate many different genes, they can influence disease progression in more than one way.