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Fall 2011

it, miRNA has been utilized quite efficiently thus far – some- when present in high amounts, it reduces the rate of cell protimes, the deregulation of a single miRNA is enough to dis- liferation and increases cell sensitivity to radiation treatment, tinguish between closely related cancers, as Dr. Jingfang Ju of establishing it as an ideal candidate for therapy. In hepatocellular carcinoma, one of the most important Stony Brook University’s Department of Pathology has found and best-understood miRNAs is the downregulated miR-122; [1]. In fact, Dr. Ju was the first researcher to discover that p53, it induces apoptosis, and also inhibits cancer growth, progresone of the most important regulatory genes in cancer, controls sion, and invasion by targeting a checkpoint miRNA expression [5]. He demonstrated that, in the mitotic cycle. Like miR-145 of gasin vitro, upregulation of certain miRNAs octric cancer, it increases cellular sensitivity curred when p53 was absent, and that levels to drugs, and is consequently a promising were low when p53 was overexpressed [6]. therapeutic target. Like colorectal cancer, Amazingly, miRNA patterns were sucboth of these cancers also contain various cessfully used to not only distinguish between oncogenic miRNAs that serve similar funcdevelopmental origins of various carcinogenic tions: deregulating growth pathways and tissues, but even between those within the intensifying proliferation [1]. same type of tissue. Lu et al. collected bone Various ways to incorporate knowlmarrow samples from patients with acute lymedge of miRNAs and their functions into phoblastic leukemia and used miRNA analytreatment are presently being investigated. sis to successfully cluster them according to Given that countless problems leading to developmental lineage, proving that “miRNA carcinogenesis are spurred by a downreguexpression patterns encode the developmental lation of miRNAs, the logical approach is history of human cancers” [4]. to stimulate expression. In a study where These are the facts, but how can we make cancerous bladder cells were treated with these miRNAs work for us? There are over a 5-Aza-CdR, an inhibitor of DNA meththousand miRNAs, and the network between ylation, and 4-phenylbutyric acid, a comthem and various mRNAs must be unimaginpound that restores and stabilizes wild type ably complex. It is the perfect labyrinth – perprotein structure, miR-127 expression was haps even impossible to solve. Rather than atstimulated, thereby causing inhibition of tempting to document this web of connections, the oncogenic BCL6 protein. scientists have taken a different approach: obTreatment with just 5-Aza-CdR was serving the miRNAs individually. enough to stimulate expression of miR-148 Colorectal cancers in various patients have and several other miRNAs useful in prevenshown consistency with regard to the downtion of metastasis. Furthermore, some gene regulation of miR-145 and miR-192 and uptherapies using viral vectors containing the regulation of miR-20, miR-21, miR-31, and gene of interest are showing auspicious remiR-99b, suggesting a conserved pathway for sults. When expression of miR-26a is ineach of these miRNAs. Upon further observatroduced into cancerous cells through such tion, miR-145 was shown to inhibit cell proa vector, the result is cellular apoptosis and liferation, specifically by inhibiting the insulin inhibition of proliferation [7]. receptor substrate 1 (IRS-1) protein, which is In prostate cancer, miR-205 and miRcrucial in mitogenic pathways. The upregulat31, two downregulated miRNAs, have been ed, and therefore oncogenic, miR-21 has been pinpointed to increase cellular sensitivity to associated with metastases, as well as high apoptosis induced by chemotherapy, and are tumor resistance to chemotherapy and a low currently valuable targets for treatment [8]. chance of survival. Regarding non-small cell lung carcinoma, Therefore, observation of the many dereguchemotherapy often fails because it causes lated miRNAs in cancer patients can provide selection for resistant cells; forcing expresinsight into the development of the tumor and sion of miRNAs that increase sensitivity to even the likely prognosis. Additionally, miRchemotherapy is an encouraging solution NA circulating throughout the plasma can be [9]. used in relatively non-invasive tests for diagIn the foreseeable future, miRNAs are nosis. For example, the presence of downregulikely to become exceptional tools for both lated miR-92 is unique to colorectal cancer, Figure 2. The secondary structure of the diagnosis and treatment of cancer. and can thus be used to distinguish it from miR-122, 85 nucleotides in length. However, many aspects of miRNA remain other diseases with comparable symptoms [1]. enigmatic – for example, the method by Various cases of gastric cancer also show which these molecules are downregulated in various cancers similarities in deregulation that seem to be, for the most part, continues to confound scientists. universal. The downregulated miR-415 is a prime example –


The Stony Brook Young Investigators Review, Fall 2011

Profile for younginvestigators

Fall 2011  

Fall 2011