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Until 9 years ago, scientists did not know that microRNAs (miRNAs) were present in cells. Since that discovery, they've learned that miRNAs control about half of all genes that are expressed in our cells, according to Nobel Laureate Phillip Sharp, PhD, institute professor of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology in Boston. He moderated a news conference on several abstracts involvingmiRNAs at the April American Association for Cancer Research (AACR) Annual Meeting in Washington, DC.

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Illustration 1. Panelists Bovell, Dr. Hernando, Dr. Liu, and Rehman (left to right) presented research at a miRNA news conference at the AACR Annual Meeting.

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MicroRNAs encode small RNAs that regulate gene expression and can help with classification, diagnosis, and prognosis in cancer. Researchers have learned that approximately 1000 different known genes encode these miRNAs, which can change into cancer and potentially be used as targets for treatment. Scientists have found that overexpression of specific miRNAs correlates with metastatic tumor growth in some cases, whereas in others it is exactly the opposite—the loss of certain miRNAs contributes to malignancies. “We look forward to the daywhenwe can either use it diagnostically or introduce small RNAs that are 20 units long,easy tomake, and easy to design into cells to have a the rapeutic effect and potentially treat cancer,” Dr. Sharp says.

The miRNA studies presented at the meeting include:

  • Expression of certain genes is associated with poor colorectal cancer prognosis. Researchers at the University of Alabama at Birmingham found that 1 set of miRNAs was associatedwith a poor prognosis for colon cancers for both black and white patients, whereas another set was associated with poor outcomes for black patients only.

    In examining a panel of 5 miRNAs in 104 black patients and 114 white patients, researchers found that miR-20a, miR-21, miR-106a, miR-181b, and miR-203 were present at higher levels in colorectal cancers than in noncancerous tissue. Increased levels of miR-181b and miR-203 were linked with shorter survival among blacks but not whites. For both groups, increased expression of miR-21 and miR-106a was linked to poor survival. “We need to evaluate a larger cohort of both races to establish the true prognostic value of all these markers and to validate our findings,” notes Liselle Bovell, a graduate student in the lab of Upendar Manne, PhD, associate professor of pathology at the University of Alabama. “We still need to look at the molecular mechanisms to see exactly how they're producing their effects, but ethnicity should be considered along with other factors.”

  • Some miRNAs contribute to melanoma brain metastasis. About 40% to 60% of melanoma patients will develop brain metastases, which have a poor prognosis and for which there is no current effective treatment, notes Eva Hernando, PhD, assistant professor of pathology at the New York University School of Medicine in New York.

    Dr. Hernando and colleagues observed low expression of specific miRNAs in brain metastases compared with metastases to other sites. This finding may enable scientists to identify high-risk individuals for surveillance and also possibly use specificmiRNAs as therapeutic targets,she says. Because little is known about the molecular mechanism that enables melanoma's spread to the brain, the team looked into specific miRNAs in vitro and in mice. Some miRNAs increased the metastatic properties of melanoma cells and their ability to adhere to brain endothelial cells, whereas other miRNAs aided cells'ability to pass through the blood-brain barrier.

  • miRNA31 represses specific tumor suppressors in lung cancer. Researchers at Dartmouth Medical School in Hanover, New Hampshire, found that miRNA31 was over expressed in mouse and human lung cancers and that it repressed specific tumor suppressors. In fact, miRNA31 was associated with a more than 5-fold increase in lung cancer versus normal tissue. Three miRNAs were significantly over expressed in most of the human lung cancers, but only the knock down of miRNA31 caused suppression of tumor growth in vitro and in vivo, says Xi Liu, PhD, graduate student in pharmacology and toxicology at Dartmouth. miRNA31 appears to be a target to suppress for lung cancer therapy.

  • miRNA21 upregulation in breast cancer cells leads to trastuzumab resistance. Scientists have identified an miRNA that may help identify patients who will respond well to trastuzumab (Herceptin). Patients with HER2-positive breast cancer often receive trastuzumab,but only about 35% of thosewho receive it as a single agent respond to therapy. Researchers at the University of Texas M.D. Anderson Cancer Center in Houston, Texas, found that breast cancer cells with increased miRNA21 caused phosphatase and tensin homolog loss, which led to trastuzumab resistance. “We also saw that when we inhibited the expression of miRNA21 there was an increased sensitivity to Herceptin treatment,” says Sumaiyah K.Rehman, a graduate student in the lab of Dihua Yu, MD, PhD, at M. D. Anderson. Because trastuzumab has been linked to heart problems in 2% to 7% of patients, this knowledge may help spare certain patients from the side effects of unnecessary treatment, Dr. Yu adds.