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Dec 1, 2009 (Vol. 29, No. 21)

microRNAs Inform Cancer Research

Alterations in the Expression of miRNA Genes Contribute to Pathogenesis on Broad Basis

  • MicroRNA (miRNA) has a significant role in controlling developmental and cancer processes like cell proliferation, differentiation, cell cycle, apoptosis, and metastasis. This ubiquitousness and their recently revealed role as key regulators of gene expression during development has boosted their use as agents in the fight against cancer. It’s a hot topic “and it’s getting hotter,” said Frank Slack, associate professor of molecular, cellular, and developmental biology at Yale University, at the Keystone Symposium “MicroRNA and Cancer” held earlier this year.

    According to Curtis Harris, M.D., chief, laboratory of human carcinogenesis at the NIH, “throughout the community, there is a lot of interest in translational science, which you can see from the number of papers published in the last few years.”

    It’s generally accepted that alterations in the expression of miRNA genes contribute to the pathogenesis of most, possibly all, human malignancies. “We found that these alterations can be caused by various mechanisms, including deletions, amplifications, or mutations involving miRNA loci, epigenetic silencing, or the dysregulation of transcription factors that target specific miRNAs,” noted Carlo Croce, M.D., director of human cancer genetics at the Ohio State University Comprehensive Cancer Center.

    “Because malignant cells show dependence on the dysregulated expression of miRNA genes, which in turn control or are controlled by the dysregulation of multiple protein-coding oncogenes or tumor suppressor genes, these small RNAs provide important opportunities for the development of future miRNA-based therapies.”

    At the meeting, Dr. Croce presented some of his group’s discoveries on the role that miR-21 plays in the EGF receptor pathway in cancer. “It’s an interesting issue; there is either loss of expression or overexpression of miRNAs in cancer. We found in particular that miR-21 is dysregulated in six out of six solid tumors.

    “We have found dysregulation of miR-21 in 13 out of 13 different types of malignancies. By microarray and RT-PCR, we now know that miRNAs are dysregulated by pathways that are involved in cancer. The fact that miRNAs are downstream targets of pathways involving cancer provides tremendous opportunity for therapy.  Many components of the pathway causing cancer may be undruggable. On the contrary, miRNAs that are downstream targets are druggable.”

    Dr. Croce showed that the global expression of miRNA indicated specific signatures for every human cancer. “We did a systematic study and discovered how each miRNA is dysregulated, and discovered signatures for early and late stages of human cancer. In the future, we’ll use this information to develop miRNA therapies.”

  • Inflammation

    Dr. Harris’ group is focused on the molecular epidemiology of human cancer and clinical biomarkers of cancer diagnosis, prognosis, and therapeutic outcomes, and miR-21 is of particular interest. “miR-21 is associated with both lung cancer and the epidermal growth factor (EGF) pathway,” said Dr. Harris. He noted that a particular area of clinical interest is EGF’s binding receptor EGFR and its role in lung cancer in women who are nonsmokers.

    “miR-21 is increased in lung cancer and at least 13 types of cancer. As initially discovered by Dr. Croce and George Calin at Ohio State University, miR-21 is over-expressed in many cancers. So from a predictive prognosis standpoint and promising preclinical studies, miR-21 is a key therapeutic target for future clinical studies.

    “There are many links between inflammation and cancer, and studies have shown that inflammation predisposes the development toward cancer,” he added. “We are especially interested in early-stage colon cancer. Some of our work, which was previously published in JAMA, looked at changes in miR-21 and found that those changes were predictive of prognosis and therapeutic outcome. We decided to put both miRNA and inflammatory gene biomarkers together and asked the question, ‘Do you get a better prognostic indicator?’ And the answer is yes, you do.” 

    Dr. Harris’ group is also investigating the interaction between nitric oxide (NO) and p53 as a crucial pathway in inflammatory-mediated carcinogenesis and has shown that NO induces ATM- and ATR-dependent p53 post-translational modifications leading to a p53 stress response in human cells in vitro, which can modulate the risk of cancer in colon tissue from patients with ulcerative colitis or Crohn’s, both of which are cancer-prone, chronic inflammatory diseases.

    In the future, miRNA studies need to “investigate a larger number of patients, comparing cancer biomarkers across ethnic groups so there’s a large body of data to analyze,” noted Dr. Harris. “It’s also time to do prospective studies; most of the reported studies have been retrospective. In the field of miRNAs, more and more people are getting involved every day. And the results are translating rapidly into the clinic. There is a lot of commercial interest in this area."

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