Functional microRNAs in Alzheimer's disease and cancer: differential regulation of common mechanisms and pathways - PubMed (original) (raw)
Functional microRNAs in Alzheimer's disease and cancer: differential regulation of common mechanisms and pathways
Kelly N Holohan et al. Front Genet. 2013.
Abstract
Two of the main research priorities in the United States are cancer and neurodegenerative diseases, which are attributed to abnormal patterns of cellular behavior. MicroRNAs (miRNA) have been implicated as regulators of cellular metabolism, and thus are an active topic of investigation in both disease areas. There is presently a more extensive body of work on the role of miRNAs in cancer compared to neurodegenerative diseases, and therefore it may be useful to examine whether there is any concordance between the functional roles of miRNAs in these diseases. As a case study, the roles of miRNAs in Alzheimer's disease (AD) and their functions in various cancers will be compared. A number of miRNA expression patterns are altered in individuals with AD compared with healthy older adults. Among these, some have also been shown to correlate with neuropathological changes including plaque and tangle accumulation, as well as expression levels of other molecules known to be involved in disease pathology. Importantly, these miRNAs have also been shown to have differential expression and or functional roles in various types of cancer. To examine possible intersections between miRNA functions in cancer and AD, we review the current literature on these miRNAs in cancer and AD, focusing on their roles in known biological pathways. We propose a pathway-driven model in which some molecular processes show an inverse relationship between cancer and neurodegenerative disease (e.g., proliferation and apoptosis) whereas others are more parallel in their activity (e.g., immune activation and inflammation). A critical review of these and other molecular mechanisms in cancer may shed light on the pathophysiology of AD, and highlight key areas for future research. Conclusions from this work may be extended to other neurodegenerative diseases for which some molecular pathways have been identified but which have not yet been extensively researched for miRNA involvement.
Keywords: Alzheimer’s disease; cancer; microRNA; pathways.
Figures
FIGURE 1
MiRNA generation and function. The nuclear transcript pri-miRNA is several kilobases in length; this transcript is cleaved by the microprocessor complex (DCGR8 and Drosha), which yields a short (~65 nucleotide) stem-loop pre-miRNA. This is transported out of the nucleus by Exportin 5 (Exp5) to the RNA-induced silencing complex (RISC) and cleaved by DICER1 (targeting the hairpin loop), generating a ~22 nucleotide miRNA duplex; one-strand is degraded, and the remaining strand is loaded into human immunodeficiency virus-1 transactivating response RNA-binding protein (TRBP)-recruited EIF2C2, also known as Argonaute 2, which then inhibits translation of target messenger RNAs (mRNAs;Bartel, 2004;Gregory et al., 2004, 2005;Chendrimada et al., 2005;Maniataki and Mourelatos, 2005;Kim et al., 2009;Rusca and Monticelli, 2011).
FIGURE 2
MicroRNA involvement in the amyloid pathway appears to contribute to AD. BACE1 mRNA expression appears to be redundantly regulated by multiple miRNAs (including predicted miR-9, not shown); APP mRNA expression is also regulated by miRNA. More miRNA binding sites have been bioinformatically predicted for both mRNAs, indicating that this regulatory mechanism is most likely very tightly regulated (Schonrock et al., 2012). Solid lines indicate known interactions; dashed lines indicate measured correlations.
FIGURE 3
Molecular and cellular pathways important to AD and cancer: increased levels of inflammation and oxidative stress have been positively associated with cancer and AD. Angiogenesis is considered one of the hallmarks of cancer, and has also been shown to be triggered by amyloid in AD (Hanahan and Weinberg, 2000;Biron et al., 2011). Proliferation and pro-survival pathways have been shown to be positively associated with cancer and negatively associated with AD. Immunity has been shown to be both positively and negatively correlated with cancer (“immunoediting”), in addition to being positively correlated with AD. The amyloid pathway does not appear to be involved in cancer pathways, so for the purposes of this review is specific to AD. Blue lines indicate interactions found in AD research; orange lines indicate interactions found in cancer research.
FIGURE 4
Summary of miRNA pathway relationships in cancer and AD. Major pathways are listed; dots indicate evidence that a specific miRNA is involved in a particular pathway. Red indicates evidence from cancer research, blue from AD research, and purple from both cancer and AD.
FIGURE 5
MicroRNA involvement in the inflammation, innate immunity, and oxidative stress pathways in AD and cancer. This pathway has been validated by several studies in AD; however, additional evidence from cancer research points to more molecules which may be involved. Blue lines indicate interactions and effects found in AD research, orange lines indicate interactions and effects found in cancer research, and black lines indicate findings common to both diseases. Dashed lines indicate downstream effects.
FIGURE 6
Redundant miRNA mechanisms regulating proliferation and survival pathways in cancer. Expression of transcription factors, BCL-2 family genes and inhibitors, and cell cycle regulatory molecules is redundantly regulated by miRNAs in cancer, prompting speculation about possible regulatory roles of these miRNAs in a similar pathway in AD.
References
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