BCL2 functions to block apoptosis by inhibiting mitochondrial cytochrome C release necessary to activate the caspase pathway of enzymes responsible for directing programmed cell death [ , ].
Computer algorithms and proteomic analysis predict a variety of targets linked to cell growth, cell cycle and apoptosis [ , ]. However, it is unclear whether these are direct or indirect miRNA targets. MiR is a relatively new member of the oncogenic miRNA group. Initially found to be over expressed in human glioblastoma tumors, miR was described as an anti-apoptotic factor predicted to down regulate genes associated with advancing apoptosis [ ].
Subsequently, miR over-expression was observed in a variety of human cancer, including those derived from breast, colon, liver, brain, pancreas and prostate [ , - ].
MiR repression of these tumor suppressor genes promotes cell transformation, tumor growth, invasion, and metastasis [ , , - ]. Translational repression of PTEN by miR leads to an accumulation of PIP3 that over stimulates the Akt pathway, activating multiple downstream pathways that stimulate cell growth and survival [ , , ]. Additionally, loss of PTEN is associated with an increase in focal adhesion kinase FAK activity that promotes cell migration and metastasis by increasing the expression of several matrix metalloproteases [ , , ].
TPM1 is an actin binding protein involved in the control of anchorage-independent growth and cellular microfilament organization [ , ]. It is hypothesized that miR repression of TMP1 leads to cytoskeleton changes that promote neoplastic transformation, cell invasion and metastasis [ ].
Similarly, repression of PDCD4 and mapsin are thought to promote cancer progression by promoting cell invasion and metastasis [ , , , ]. There are multiple proposed mechanisms of PDCD4 and mapsin action, all of which are still under investigation. Both molecules are associated with apoptosis and regulation of the urokinase receptor uPAR , which is involved in degradation of the extracellular matrix [ , - ]. Thus implicating a role in tumor progression and metastasis.
The miR miRNA cluster is the most complex. The sequence and organization of the miR cluster is highly conserved among all vertebrates examined [ ]. In humans, the cluster produces six mature miRNAs miR, miRa, miRa, miRb-1, miRa and miR from a polycistronic transcript generated from the third exon of the open reading frame C13orf25 at loci 13q MiR can be directly regulated by c-myc and E2F transcription factors E2Fs but, E2F3 is thought to be the predominant regulator [ 67 - 69 , ].
Evidence supports a dual role for miR as both an oncogene and a tumor suppressor. However, the miR functional network is extremely complex and remains under extensive investigation. MiR is most commonly thought of as an oncogene [ ]. The 13q Additionally, over expression of c-myc is commonly observed in human cancers, which would result in an increase in miR expression [ - ].
E2Fs are critical regulatory components for apoptosis and cell proliferation [ - ]. However, isoform specificity is apparent. E2F1 is primarily involved in promoting apoptosis and E2F3 signals more specifically for proliferation [ 68 , 69 , ].
The crucial balance of E2F isoform expression modulates apoptosis and proliferation in normal cells. E2Fs stimulate the transcription of their own genes and of their regulators, c-myc and the miR cluster.
This creates an E2F positive auto-regulatory feedback loop which is controlled by miR in a negative feedback loop [ 67 - 69 , , ]. Additionally, c-myc regulates E2Fs and miR, establishing a double feed-forward loop [ 68 , ].
The oncogenic activity of miR is hypothesized to promote tumorigenesis by selectively repressing E2F1. Over expression of miR would decrease E2F1 levels needed to induce apoptosis.
This does not trigger the negative feedback loop because E2F3 is the predominant miR regulator instead there is an increase in E2F3 levels that will stimulate proliferation. Although the majority of data supports miR as an oncogene there is some evidence that it also acts as a tumor suppressor. Coincidently, loss of heterozygosity and deletions at 13q AIB1 is a coactivator that increases the activity of transcription factors and various steroid receptors, which are involved in breast cell proliferation, growth and hormone signaling [ - ].
In this cellular context miRp is a tumor suppressor that regulates proliferation, growth, survival, differentiation and anchorage-independent growth by inhibiting AIB1 translation [ - ]. Since their discovery, miRNAs have provided a new perspective on regulation of gene expression. Extensive research over the last decade revealed that miRNA are more prevalent that originally thought, with miRNA identified to date in humans and over predicted [ 9 - 11 , ].
Although, much more investigation is required to determine all miRNA targets, silencing mechanisms and networks it is accepted that miRNAs play an integral role in regulating an array of fundamental biological processes. Evidence indicates that miRNA dysregulation is associated with disease, notably cancer as miRNA can function as oncogenes and tumor suppressors. MiRNAs are currently being exploited to advance cancer diagnosis, classification, prognosis and treatment [ 30 ].
MiRNA profiling was originally done with glass slide microarrays [ - ]. New advances have lead to the development of bead-based technology, specifically bead-based flow cytometric expression and bead-array profiling which is highly accurate, specific and feasible to implement within a clinical setting [ 31 , ]. This technology, and other techniques including quantitative reverse-transcriptase polymerase chain reaction qRT-PCR , can identify distinct miRNA expression patterns that can characterize specific tissue and disease states, distinguishing between subtypes of normal and malignant tissues [ , , ].
MiRNA signature profiles can be used to determine prognosis [ - ], response to drug therapy [ ], predict treatment efficiency [ , ], race susceptibility [ 23 ] and patient susceptibility to cancer and metastasis [ - ]. This has been demonstrated with lung cancer where unique miRNA profiles can distinguish between normal lung and tumor tissue and correlate to patient prognosis [ ].
Additionally, miRNA profiles can discriminate between normal and malignant B-cells in chronic lymphatic leukemia and could hypothetically be utilized to classify undifferentiated tumors to their organ of origin [ ].
Initially miRNA profiling was conducted on samples extracted from tissues. However recent studies have found stable miRNAs in readily available body fluids including, serum [ , ], plasma [ - ], urine [ ] and saliva [ ]. The source of the endogenous circulating miRNAs is unclear. The predominant hypothesis suggests that miRNAs more likely pre-miRNAs are circulating in exosomes that are shed from normal or tumor-derived cells [ ]. Containment of miRNAs pre-miRNA within exosomes would protect the molecules from degradation and explain the molecules stability, even in harsh experimental conditions [ , ].
However, a combination of other theories collectively suggest it is possible that the circulating miRNAs are from lysed cells and their stability is due to binding of DNA, proteins and or lipids that protect them from degradation [ , , ].
Although the use of miRNAs as biomarkers in body fluids is exciting there are limitations that need to be overcome before there is wide-spread clinical application. It would appear classification of miRNAs would be necessary to account for different miRNA profiles that may arise depending on race, gender and age.
The effects of cancer treatment, whether it be chemotherapy, surgery, radiation or a combination of these methods, should be investigated as it will presumably change miRNA profiles. One particular study showed specific reduction of miR plasma levels following surgical resection of squamous cell carcinoma of the tongue [ ].
Additionally, the mechanism of miRNA released into these body fluids needs to be characterized. Within the clinical setting the technological approach needs be standardized as a variety of handling and processing factors can results in dramatics changes in miRNA profiles [ ].
Establishment of universal profiling approaches for specific samples i. Further research exploring the outcome of therapeutic treatment associated with different miRNA profiles could provide valuable information to advance drug regime selection. A recent study of patients with colon adenocarcinoma receiving fluorouracil-based chemotherapy revealed that high miR expression is associated with a poor therapeutic outcome [ ]. It is possible other chemotherapy drugs might have a better outcome in comparison to fluorouracil.
As we gain understanding of specific miRNA mechanisms and function it could become evident that certain chemotherapeutic drugs might be favorable based on their mode of action in relation to a particular miRNA profile.
MiRNA modulation is emerging as a novel therapeutic target with the use of antagomirs. Antagomirs are chemically engineered oligonucleotides that inhibit miRNA target binding through competitive miRNA binding [ 14 ]. A study conducted in vivo with mice utilized this novel therapeutic approach to inhibit miR expression. Intraperitoneal injections administered the antagomirs to the liver successfully inhibited miR liver expression, which decreased plasma cholesterol levels in normal and obese mice [ 13 ].
Thus miR may be a good therapeutic target for hepatic metabolic diseases. This study suggests that antagomirs could be employed as a new treatment because they are long lasting, specific and have no significant associated toxicity. However, there are still many limitations associated with antagomirs as a therapeutic treatment for humans.
Firstly, miRNA sequences and targets need to be further characterized and cataloged. MiRNAs can have multiple targets and a full understanding of their functional mechanisms would be required to design appropriate antagomirs. Although computational bioinformatics programs have made great improvements they still do not have a high enough accuracy to predict miRNA targets [ , ].
Secondly, an effective method of delivery has yet to be developed for humans. High-pressure injection and electroporation can effectively delivery small RNAs, but they cause unwanted tissue damage [ - ].
A variety of viral vectors can efficiently introduce small RNA into cells [ - ]. While some vectors have been useful in animal studies they are not ideal for human because they can elicit an immune response that deflates their effectiveness [ - ].
Vectors that integrate into the genome can cause further problems with mutations associated with genome insertion [ , ]. Progress is also being made in the expanding field of nanobiotechnology to develop a means to package and deliver RNA to specific sites [ - ]. Viral vectors are being modified to improve expression specificity and make them safer for human trials [ , ].
The young field of miRNA research is continually expanding. Current and future investigation will hopefully provide the much need information to sufficiently characterize the targets and functional mechanisms of miRNAs. A deeper understanding of miRNA molecular pathways would provide great insight in the initiation and progression of cancer, among other diseases and is essential to advance therapeutic treatments. National Center for Biotechnology Information , U.
Journal List Curr Genomics v. Curr Genomics. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Open in a separate window. MicroRNA maturation and function. Nuclear component of microRNA biogenesis. Cytoplasmic component of microRNA biogenesis. Slicer-Dependent Silencing Fig.
Slicer-dependent microRNA mediated gene silencing. Slicer-Independent Silencing Fig. Slicer-independent microRNA mediated gene silencing. P-Bodies P-bodies are dynamic small cytoplasmic protein spheroid domains found in cells ranging from yeast to humans [ , ]. The P-Body Model Fig. The P-body model. Proposed microRNA working model. MicroRNA IN CANCER Cancer is a multistep process in which normal cells experience genetic changes that progress them through a series of pre-malignant states initiation into invasive cancer progression that can spread throughout the body metastasis.
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A novel RNA splicing-mediated gene silencing mechanism potential for genome evolution. Mammalian mirtron genes. Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia. Intronic microRNA precursors that bypass Drosha processing. In , another group published their results obtained from volunteers drinking watermelon juice or eating mixed fruits watermelon, banana, apple, orange, grape, mango and cantaloupe [ ].
Using real-time reverse transcription polymerase chain reaction RT-qPCR and northern blotting, they identified 10 plant miRNAs in human plasma at high basal levels [ ]. By conducting a kinetics study, they proved that the absorption of plant miRNA was not a technical artifact or contamination, but a real physiological event.
Importantly, they established a standard operation procedure for measuring plant miRNAs in human and animal plasma, which would promote investigations in this nascent field. Studies supporting biologically relevant uptake of plant-originated miRNAs have focused on miR, a honeysuckle-derived miRNA [ 29 , , , , ].
Honeysuckle is a well-known Chinese herb widely applied in the prevention and control of epidemic diseases. Modern pharmacological study has confirmed that honeysuckle has a broad spectrum of antimicrobial activity [ ]. Zhang et al. More interestingly, miR was not degraded during the honeysuckle boiling process [ 29 ]. This phenomenon was consistent with a simulation study, in which dietary plant miRNAs were stably present in intact form after storage, processing, cooking and early digestion [ ].
They also demonstrated that the bulk of miR in mouse peripheral blood was detected in MVs fraction and largely associated with the Ago2 complex, implying miR might exert its function through the same MV-mediated pathway.
Concerning the stability of miR, it was proposed to rely on its unique sequence and high GC content. More insightful knowledge of miR was put forward by four independent studies from Yang et al. Consistently, Yang reported a significant increase of plant miR in the sera and urine of the honeysuckle decoction-consuming mice [ ].
Moreover, the damaged guts resulting from cisplatin also led to enhanced miRNA retention in the mouse circulation [ ], which further verified the possibility of miRNAs transferring from plant to animals. Additionally, they showed that unlike most of plant-derived biomolecules, miR was atypical as their abundance was positively correlated with the degradation of plant foods and rRNAs ribosomal RNAs , and their biogenesis was Dicer independent [ ].
The above information suggests that miRNAs may be one of the hidden but bioactive components in herbal medicines. The potentials for therapeutic use of plant miRNAs were also supported by studies from other labs [ , , , ]. One group reported that the oral administration of a cocktail of three tumor suppressor miRNAs designed to mimic sRNAs produced in plants reduced tumor burden in a mouse model of colon cancer [ ].
Another group showed that plant-derived miR could be predominantly detected in Western human sera and tumor tissues, and was associated with the incidence and progression of breast cancer [ ]. Their study suggested that plant-engineered miRNA designed for specific targets possessed a significant potential in clinical therapeutic applications [ ]. Supportively, Cavalieri et al. This study consolidated the therapeutic capacity of plant miRNAs in the prevention of human disorders.
These studies suggest that miRNAs derived from plants or diets can not merely transfer to animals effectively, but exert their gene-regulatory function in a cross-kingdom manner. Dickenson et al. Unfortunately, little or no plant miRNAs or miRa were detected in the blood or liver of mice fed with rice-containing diets. Interestingly, consistent with the result of Zhang [ 28 ], the levels of LDL in the mice liver were indeed increased in mice fed with uncooked rice, but the expression of LDLRAP1 remained unchanged across all three experimental groups.
They therefore proposed that the increase in LDL levels reported by Zhang et al. Using recently developed deep sequencing technologies and bioinformatic analysis, another two groups [ , ] found variable amounts of plant miRNAs in public animal sRNA datasets. Among them, the most abundant molecule was miRa, having a sequence typical of monocot plant species. Additionally, Zhang et al. Based on experimental evidences proposing that cross-contamination during library preparation was an unnoticed source of exogenous miRNAs, Tosar et al.
Besides, negative results regarding cross-species transmission of plant-derived miRNAs were obtained in various insects and animals [ , , , ]. Study by Baier et al. Consistently, Snow et al. However, after ingestion of fruits full of listed plant miRNAs, all of investigated subjects did not carry detectable plasma levels of those molecules [ ].
Similar negative findings were shown for Macaca nemestrina, a non-human primate model employed by Witwer et al. Although they observed low concentrations of some investigated plant miRNAs, the amplification was variable and might be non-specific. Recently, another research group aimed to detect corn miRNAs in cecum, feces, liver and in whole blood of mice [ ].
Similar to the studies discussed above, Huang and colleagues [ ] failed to identify corn miRNAs in the mentioned organs following supplementation of corn miRNAs in animal diet or gavage to the animals. Further in vitro digestion system suggested that degradation of miRNAs was responsible for the observations [ ].
Taken together, these independent investigations certified little or low measurable uptake of plant miRNAs in human and other mammals after consumption of plants or plant miRNAs and unfolded crucial problems existing in the study of cross-kingdom transmission of miRNAs. The main stream of pitfalls claimed by dissenters is the reliability and sensitivity of techniques commonly applied in the study of cross-kingdom transmission of miRNAs.
Firstly, contamination of endogenous miRNAs from recipients or study platforms could not be ruled out. Thus, a standard and consensus experimental protocol, which truly makes plant and animal miRNAs distinguishable, and accurate experimental performance in the absence of any known sources of plant contaminations are both highly recommended.
Secondly, noises of background signals during RT-qPCR or artifacts from sequencing procedure raise great concerns, especially when low signals from target miRNAs were detected. This technical flaw necessitates reliable negative control groups and double-confirmation of positive results using independent methodologies.
Thirdly, selection of relevant experimental controls gives rise to some discrepancies. A comprehensive design, application and analysis of more than one control group may assist to reduce the disagreement. Lastly, direct evidence of plant-originated miRNAs crossing GI may compromise the divergences existing in this field. In the case of miRNAs from rice or herbal medicines, high-temperature processing such as cooking or boiling are unavoidable, in which miRNAs may be largely destroyed.
In addition, the existence of RNases, phagocytosis and extreme pH in GI tract as well as blood circulation may also destabilize ingested miRNAs prior to their access to recipient cells. Otherwise, the increased stability may also be explained by the unique sequence and GC content of plant miRNAs. The most prominent example is honeysuckle-derived miR [ 29 ], as mentioned above.
It has been reported that above listed vesicles could protect extracellular miRNAs against RNases on one hand, and on the other hand facilitate their transfer within the host [ , ].
In , Mu et al. Their data suggested that EPDENs were uptaken by intestinal macrophages and stem cells when orally administrated, and actively exerted biological functions on the recipient cells. This finding potentially implied EPDENs as possible mediators in the crosstalk between the plant kingdom and mammalian cells. Additionally, stabilization of extracellular miRNAs was proved to be associated with RNA-binding proteins, such as nucleophosmin 1 [ ], high-density lipoproteins HDL [ ] and Ago-2 [ ].
Plant-based foods or herb materials like in the form of decoctions are abundant in miRNAs, which are potentially packaged into vesicles or incorporated with proteins. Being absorbed by gut lining, miRNAs enters circulation. If unfortunate, these circulating miRNAs may be filtrated and excreted at the kidney prior to their access to recipient cells.
By using an ex vivo everted gut sac to simulate the real physiological condition, a recent study by Luo et al. Meanwhile, SID-2 is another recently identified transmembrane protein in C. In contrast to the ubiquitous expression of SID-1, SID-2 is expressed in the intestine luminal membrane and might mediate the endocytosis of sRNAs from the lumen [ ].
It is commonly believed that intestinal epithelial cells IECs form a continuous physical barrier in mammals, which provides a severe impediment against the uptake of environmental sRNAs [ ]. Evidence to date defines two possible modes of transport across the digestive tract epithelium, either transcellular or paracellular.
During the transcellular pathway, miRNAs could cross the intestine via transcytosis or protein transporters. Alternatively, some vesicles such as microvesicles or exosomes could also fuse with the epithelial cell membrane facilitating transportation. Additionally, for ribonucleoprotein complexes containing sRNAs, endocytosis has been shown to play a role in the uptake of sRNAs from dietary sources.
On the other hand, the paracellular pathway allows diffusion of molecules in the space between epithelial cells. This mode of transfer is usually under a delicate regulation of intercellular tight junctions [ ]. Supportively, Yang et al. In addition to intestinal epithelial cells [ ], the mammalian digestive tract is colonized by a variety of immune cells, which are able to trap sRNAs and other molecules on one side and release them on the other, with or without movement of the cell to a new location [ ].
During these processes, plant miRNAs are released from destroyed cells and transferred to the intestinal epithelial cells, where plant miRNAs could be selectively incorporated with proteins or packaged into vesicles. Once delivered to targeted cells and engulfed, plant miRNAs are liberated and subsequently execute their functionalities. Hormones are chemicals secreted from glands and enter the bloodstream where they circulate until exerting an effect on a downstream target cell.
Both animal and plant cells use hormones for long-distance communication. Recent findings suggest circulating miRNAs as a novel form of cell-to-cell communicator [ , ]. This viewpoint is reflected by the fact that circulating miRNAs are secreted by donor cells into circulation, then stably transported to other parts of the body and up-taken by recipient cells [ ].
The reveal of hormone-like actions of miRNAs in recipient cells has driven this notion forward. Skog et al. In another study, miR was indicated to modulate immune responses during the unidirectional transfer from T cells to antigen-presenting cells APC [ ]. These results highly suggest that secreted miRNAs represent a novel mode of signaling for long-distance transportation of messages, by which donor cells can influence gene expression of recipient cells, and thus impact physiological and pathological processes.
With the discovery of circulating miRNAs in human body fluids, a more intricate level of cellular communication and regulation is introduced, and interactions between hormones and miRNAs are starting to emerge. Considering the significance of miRNAs and their involvement in various biological processes, it is not surprising that miRNAs are participating in the synthesis [ , ] and secretion [ ] of several hormones. Likewise, the expression of several miRNAs is in turn under regulations of hormones.
A finding has reported the role of miRNAs in adrenal cell physiology [ ]. Angiotensin Ang II, the end product of the renin-angiotensin system, has been confirmed to up-regulate the expression of miR in human adrenocortical cells HR [ ].
Notably, in microarray analysis of more than miRNAs, only the expression level of miR has been up-regulated by Ang II, and its overexpression caused an increase in aldosterone secretion and cell proliferation [ ]. Another study showed that hormones could regulate miRNAs in the testis, ovary, and adrenal glands steroidogenic cells and the expression level of adrenal miRNAs appears to be regulated by more than one hormone [ ].
Thyroid hormones TH , which are known to be essential for the development, differentiation and maintenance of metabolic balance in mammals, might alter miRNA expression which could, in turn, alter mRNA abundance [ ].
Based on their data, two novel TH-regulated target genes that were downstream of miRd signaling, caudal type homeobox CDX 2 and sterol O-acyltransferase SOAT 2, have also been identified and characterized. In hypothalamus and pituitary, mounting miRNAs have been implicated as communicators interacting with hormones [ , , ].
MiR has been shown to inhibit the expression of proopiomelanocortin POMC and affect the synthesis and secretion of pituitary hormones [ ]. Investigation of miR has revealed its role in controlling the level of oxytocin, which was produced in the hypothalamic paraventricular and supraoptic nuclei [ ].
Another study has demonstrated that miRp was involved in the secretory regulation of follicle-stimulating hormone FSH in porcine anterior pituitary cell [ ]. Apart from crosstalk between hormones and miRNAs in mammals, their interactions appear to be rational in plants. The expression level of miR has been shown increased by abscisic acid ABA , a plant hormone involved in bud and seed dormancy, root growth, leaf senescence and abscission, stomata opening and stress protection [ ].
Besides, miR, miR and miR have been proven to be involved in the plant hormone gibberellin pathway [ , , ]. Hormone modulation of miRNAs in plant has been exemplified in the case of auxin. To keep normal development, change of exogenous auxin levels resulted in alterations of miR and miR levels [ , ].
Another example of this scenario involves miR and miR, which were discovered to be down-regulated when subjected to cytokinin 6-benzylaminopurine 6-BA treatment [ ]. Additionally, in the same report, Liu et al. As potent intracellular mediators, functional significance of miRNAs has been widely validated. Evidence from animals showing inter-species gene regulation mediated by miRNAs derived from evolutionarily distant species suggests miRNAs as an alternative nutrient.
Likewise, existence of miRNAs in herbal plants represents an extended scope of ingredients that may intentionally impact human health. In light of the phenomenon that synthetic supplements of phytochemicals do not usually have the same efficacy as complex herb materials, cross-species transmission of dietary miRNAs from plants to human may provide additional clues for evaluating the active therapeutic components of herbs.
To fulfill the above, a consensus justifying the methodology of miRNA verification should be reached. Since mammals do not possess amplification pathways as C. If these should be unrealistic, the exact mechanisms of intestinal absorption, bioavailability, tissue distribution and function of exogenous miRNAs could be envisaged, which though constitutes the major challenges will facilitate the development of both nutrition and medicine.
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