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Prioritizing Diagnostic, Prognostic, and Therapeutic MicroRNAs in Pancreatic Cancer: Systems and Network Biology Approaches
An Introduction and Brief Overview of MicroRNAs
MicroRNAs (miRNAs) are short noncoding RNAs 22 nucleotides in length that carry out complex regulatory functions through post-transcriptional targeting and modification. Initially, these miRNAs were discovered through analyses of Caenorhabditis elegans development, in which it was shown that the lin-4 and let-7 antisense RNAs exhibited developmental regulatory function in the organism post-transcriptionally . The miRNAs are exported from the nucleus and undergo processing from larger to smaller segments via various endonucleases . For a time, their role relative to or within cellular function was largely unknown, yet with increasing analyses of sequence complementarity, mounting evidence suggested that miRNAs function as a family formed of RNA duplexes directly capable of gene regulation post-transcriptionally .
Given the remarkable placement of miRNAs in the regulatory chain, it makes sense that a corresponding expression variance could be ascertained through different cell types or cell states. Indeed this is the case, wherein various specific types of miRNAs are found exclusively in specific cellular systems in a context-dependent manner. An example of this is the highly concentrated presence of miR-122 in the liver or miR-223 in mouse bone marrow granulocytes and macrophages . Such nuanced differences in expression levels also could be seen in stem versus differentiated cells in animal models. Recently, an experiment demonstrated the use of miR-291-3p, miR-294, and miR-295 in the enhancement of induced pluripotency, highlighting the valuable role of these molecules in normal development .
Logic stands that, given the delicate placement of miRNAs within the post-transcriptional regulatory pathway, disease development and progression could be correlated closely to aberrant miRNA function. Indeed, this is the case because erroneous expression (deregulated expression) or depletion of this class of molecules results in a concurrent defect in cellular function, ranging from contrasting phenotypic changes, such as developmental aberrations, to physiological abnormalities, such as degenerative conditions linked to malignancies .
This chapter thus explores the significance of miRNAs in disease and the various facets surrounding their relevance clinically and experimentally as well as their future implications in the ever-changing omics paradigms.
MicroRNAs and Disease Priming and Progression
Because of the intricate links of miRNAs in genetic post-transcriptional control, their aberrant behavior can be analogous to “disease priming” whereby a fine homeostatic balance is effectively disturbed, initiating the development of a disease state. Key within this fact is the very basis of many clinically presented malignancies essentially being deregulated cells, no longer able to carry out apoptosis. The miRNAs have presented themselves as regulators of many aspects of cell function, and when their mechanisms fail, they contribute to cancer development . Healthy cells thus require a cascade of events to take place dissociating the cell from its regulatory mechanisms. The miRNAs contribute to this cascade as a form of a switch that functions to activate or deactivate pathways or “microcircuits” within the regulatory schematic . These control points vary in location and function both regulating the progression and timing of cellular events as well as disrupting them in a highly regulated context-dependent fashion.
If we subdivide the process of cancer development according to the Hallmarks of Cancer scheme of Hanahan and Weinberg, then we arrive at six distinct phases of cellular function that must be analyzed synergistically: proliferative signaling, evasion, invasiveness and metastasis, replicative immortality, angiogenesis, and resisting cell death ( Figure 15.1 ) . Each of these has had miRNAs implicated in one form or another either as direct interacting partners with molecules or as part of larger feedback loops for regulatory control.
A search through any article database will yield thousands of articles highlighting the many thousands of possible mechanisms miRNAs use to exert their regulatory control over physiology. Generally, under normal conditions, many miRNAs have been shown to provide oversight, earlier characterized as microswitches. This regulatory oversight has been implicated in multiple pathways, one of which is progenitor cell proliferation and downstream function . Placed in the context of the well-studied epithelial-to-mesenchymal transition (EMT) exhibited in highly malignant cells, many of the same miRNAs were shown to exert a concerted control over crucial signaling pathways—for example, Hedgehog signaling leading to concurrent proliferation of the cells . It then becomes readily apparent that aberrations in miRNA signaling stimulate a breakdown of the regulatory cascade of cellular function from a genetic perspective. One telling example is reduced expression of the let-7 tumor suppressor miRNA through phosphorylating the human miRNA-generating complexes, which in turn mediate the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway . MAPK/ERK is particularly important because of its involvement in maintaining stem cell pluripotency . From this can be inferred further the maintenance of cancer stem cell populations contributing to the later proliferative phases of cancer but still sharing the same signaling malfunctions expressed earlier in the cell cycle . This signaling motif contributes to the self-sustainability of the cancer cells, which also enhances their ability to evade the body’s regulatory policing by responding to various stimuli. In glioma cells, an interesting relationship was established between glucose levels and the expression of miR-451 . When glucose is present, miR-451 exists at elevated levels, but when the reverse takes place, a concurrent decrease in miR-451 results in slowed proliferation but enhanced evasion in terms of migration and survival. Thus, miR-451 was established as a possible regulator of the liver kinase B1/adenosine monophosphate-activated protein kinase signaling pathway. A similar mechanism was elucidated for the PI3K/AKT pathway also in gliomas where miR-451 was downregulated, causing inhibition of cell growth and initiation of apoptosis . Interestingly, an upregulation of miR-451 expression (albeit without glucose starvation) elicited a different response in esophageal carcinoma, whereby apoptosis was initiated, and cell invasiveness and proliferation were diminished in the EC9706 cell line .
Many examples could be found in which miRNAs present themselves as important components of key regulatory pathways related to cellular communication and function . In some pathways, miRNAs exert a direct and stringent function on downstream regulators. Some of these very mechanisms are inherently important for basic physiological functions; when they are aberrant, however, they become the root causes of cancer development even when no outright phenotypic patterns are demonstrated . The same pathways involving miRNAs in their chain of function also regularly are perturbed when analyzed in patients, such as the forkhead box protein M1 transcription factor . Representing some of the complexities arising from dynamic miRNA function, it has been shown that some cancer cells have even evolved through a scheme of deleting miRNA recognition sequences evading regulation by the molecules in B-cell lymphomas . The perturbations can vary and the family of miRNA can be quite different in function, depending on their location in the body . One malfunctioning miRNA, implicated in one disease model in fact may be benign in another, and several seemingly unrelated benign miRNAs together may interact to form a disease phenotype .
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