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Mar 15, 2010 (Vol. 30, No. 6)

miRNAs' Therapeutic Potential

Scientists Scrutinize Promising Molecules as Potential Drug Targets and Biomarkers

  • Tumor Formation

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    Researchers at Eastern Virginia Medical School are analyzing how miRNAs control developmental events.

    Aurora Esquela-Kerscher, Ph.D., of the department of microbiology and molecular cell biology at Eastern Virginia Medical School, will present recent findings on the role of the let-7 miRNA family in processes related to cellular growth and differentiation. Since the early phases of carcinogenesis resemble embryonic development, often involving the re-expression of embryonic mesenchymal genes, Dr. Esquela-Kerscher explains, many of the same cellular processes used to direct appropriate embryonic development are the same mechanisms that go awry in cancerous tissues.

    Her lab focuses on analyzing how miRNAs control developmental events and how their dysfunction contributes to cancer progression using a combination of Caenorhabditis elegans and mammalian model systems to functionally characterize miRNAs.

    In particular, she and her colleagues have focused on the role of the let-7 family during cancer progression. Let-7 miRNA controls the timing of cell-cycle exit and terminal differentiation in C. elegans, she says, and is poorly expressed or deleted in human lung tumors.

    At the meeting, Dr. Esquela-Kerscher will present findings using the nematode to understand how let-7 functionally overlaps with other miRNAs, such as those belonging to the lin-4 family, to direct common developmental events associated with cancer-related pathways. For instance, animals that carry a triple deletion for the lin-4 homologue, mir-237, and certain let-7 homologues have morphological defects and fertility problems related to abnormal mitotic and meiotic abnormalities in the germline that were not found in the single- or double-deletion combinations.

    Dr. Esquela-Kerscher and colleagues have also begun to determine how the let-7 miRNA family functions as tumor suppressor genes in mammals by negatively regulating the RAS, MYC, and HMGA2 oncogenes, as well as several cell-cycle progression genes. The scientists showed that let-7 overexpression in cancer cell lines alters cell-cycle progression and reduces cell division, and reciprocally inhibiting let-7 function leads to increased cell division in A549 lung cancer cells, providing evidence that let-7 functions as a tumor suppressor in the lung.

    “Our work now shows that multiple genes involved in cell-cycle and cell-division functions are also directly or indirectly repressed by let-7. This work reveals let-7 miRNA to be a master regulator of cell-proliferation pathways.” 

    Dr. Esquela-Kerscher and colleagues at Yale University further showed that let-7 miRNA directly inhibits the growth of lung cancer cell xenografts in immunodeficient mice. Using an established orthotopic mouse lung cancer model, the investigators showed that intranasal let-7 administration reduced tumor formation in vivo in the lungs of animals expressing a G12D-activating mutation for the K-Ras oncogene.

    Dr. Esquela-Kerscher is also studying the role of let-7 outside of the lung, particularly in tissues of urothelial origin. Her lab found that let-7 is dysregulated in prostate cancer cells differing in their metastatic status, indicating a novel role for this miRNA in prostate cancer progression.

    Furthermore, she is interested in determining if let-7 and other miRNAs can be useful diagnostic and prognostic biomarkers for prostate cancer. Due to her access to a vast repository of human prostate specimens from the Virginia Prostate Center at Eastern Virginia Medical School, her lab has begun to analyze the miRNA expression profiles in FFPE specimens taken from the primary prostate tumor, normal adjacent tissue, and the lymph-node metastasis of individual prostate cancer patients, as well as in tumors from patients presenting insignificant and organ-confined cancer.

    They are also determining the “miRNA signatures” in blood, urine, and expressed prostatic secretions that were obtained from both normal and cancer patients. Dr. Esquela-Kerscher is optimistic in the future use of miRNAs for the treatment and diagnosis of a wide range of human cancers.

    “The challenge will be to effectively deliver small RNAs to the tumor and to develop reliable and affordable miRNA-based biomarkers that can be measured in the clinic using noninvasive means.”

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