The Small Side of Cancer

Can microRNAs help diagnose, classify, and stage human cancers?

David Secko
Apr 1, 2008
<figcaption>In these stained lung tissue sections, mice deficient for microRNA-155 (bottom slide) show increased build up of collagen (signifying lymphoma) versus their wild-type counterparts (top slide). Credit: Madhuri V. Warren / Sanger Institute</figcaption>
In these stained lung tissue sections, mice deficient for microRNA-155 (bottom slide) show increased build up of collagen (signifying lymphoma) versus their wild-type counterparts (top slide). Credit: Madhuri V. Warren / Sanger Institute

In 2002, George Calin, Carlo Croce, and colleagues at Thomas Jefferson University provided the first evidence that microRNAs — small noncoding RNAs that can repress gene expression — were linked to cancer.1 Since then, the field has mounted a massive effort to find out whether those links will be clinically useful.

In the Hot Papers featured here, Croce, now at Ohio State University, and his group tested the link between microRNAs and cancer on a large scale. They carried out a microarray analysis of 363 samples from six frequently found solid-tumor types in humans and 177 controls, revealing that cancer cells have distinct and abnormal microRNA profiles.2 In the second paper, the group followed up...

A common denominator

Looking at 228 microRNAs in the first Hot Paper, Croce's group found 36 that were overexpressed and 26 that were downregulated in cancer cells versus normal cells. "This and many other groups since have shown that microRNA expression profiles are essentially ubiquitously abnormal in every cancer that has been examined," says Mendell. Croce's group also found that these microRNA profiles allowed the tumors to be grouped based on their tissue of origin. This suggested that a relatively small number of microRNAs could be used as markers to classify and distinguish cancer cells.

Expression-profiling studies can also help determine which of the more than 1,000 predicted human microRNAs might be key regulators, and therefore good candidates for playing a key role in cancer. Croce's group's findings led them to focus on miR-155. In a transgenic mouse that overexpresses this microRNA, expression of this microRNA alone promoted a neoplastic phenotype.3

In addition, work on miR-155 is being extended to other realms, including inflammation. In 2007, David Baltimore and colleagues from California Institute of Technology used microarray analysis to show that miR-155 was upregulated by stimulators of inflammation, providing a potential microRNA link between inflammation and cancer.4

More recently, Mendell's group revealed that activating the Myc oncogenic pathway turns off a large subset of microRNAs to drive tumorigenesis.5 In contrast, they have also shown that the microRNA miR-34a is directly controlled by the p53 tumor suppressor pathway.6 This shows that microRNAs can act as both oncogenes and tumor suppressors, says Jeffrey Ross, of Albany Medical College.

Indeed, one of the most significant suggestions of these studies is that microRNAs comprise a downstream factor of pathways that lead to cancer. "If they are the downstream targets, and the activity of pathways depend on [the] activity or loss of expression of microRNAs, [this] makes them ideal targets for therapy," says Croce.

Oncological signposts

"There have been some early glimpses of microRNAs being useful as prognostic and diagnostic markers" for cancer, says Ross. For example, in 2008, Pan-Chyr Yang and colleagues from the National Taiwan University identified a five-microRNA profile that predicted the treatment outcome of lung cancer.7 "There is no question that many more of these studies will appear soon," says Ross.

Calin agrees. He also cites the potential role of microRNAs in cancer predisposition. In 2007, Elizabeth Raveche and colleagues from New Jersey Medical School found three loci linked to the spontaneous development of B-cell lymphoproliferative disease in a mouse model for human chronic lymphocytic leukemia.8 One of these loci turned out to be a mutated form of the microRNA miR-16-1. "For 20, 30 years, people were not finding the real causes of familial cancers except for a few examples," says Calin. "In my opinion, a lot of cancer predisposition is linked to microRNAs and other noncoding RNAs."

Mendell hopes that all these aspects of microRNAs will lead to new therapeutic strategies that target them and their pathways, but he adds: "We are still at the very earliest stages of understanding how these microRNAs have such a potent effect on cellular behavior."

Data derived from the Science Watch/Hot Papers database and the Web of Science (Thomson ISI) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. S. Volinia et al., "A microRNA expression signature of human solid tumors defines cancer gene targets," Proc Natl Acad Sci, 103:2257—61, 2006. (Cited in 181 papers) S. Costinean et al., "Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E mu-miR155 transgenic mice," Proc Natl Acad Sci, 103:7024—9, 2006. (Cited in 68 papers)

References

1. G.A. Calin, et al., "Frequent deletions and down-regulation of micro-RNA genes miR-15 and miR-16 at 13q14 in chronic lymphocytic leukemia," Proc Natl Acad Sci, 99:15524—9, 2002. 2. S. Volinia et al., "A microRNA expression signature of human solid tumors defines cancer gene targets," Proc Natl Acad Sci, 103:2257—61, 2006. (Cited in 181 papers) 3. S. Costinean et al., "Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E mu-miR155 transgenic mice," Proc Natl Acad Sci, 103:7024—9, 2006. (Cited in 68 papers) 4. R.M. O'Connell et al., "MicroRNA-155 is induced during the macrophage inflammatory response," Proc Natl Acad Sci, 104:1604—9, 2007. 5. T.C. Chang et al., "Widespread microRNA repression by Myc contributes to tumorigenesis," Nat Genet, 40:43—50, 2008. 6. T.C. Chang et al., "Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis," Molec Cell, 26:745—52, 2007. 7. S.L. Yu et al., "MicroRNA signature predicts survival and relapse in lung cancer," Cancer Cell, 13:48—57, 2008. 8. E.S. Raveche et al., "Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice," Blood, 109:5079—86, 2007.

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