cell metabolism governing the growth and functioning of each cell and a whole organism refers to chemical transformations and enzyme - catalyzed energy producing and energy utilizing reactions of carbohydrates , proteins , and lipids . amongst the most metabolically active organs are liver , brain , gut , kidneys , and heart [ 13 ] .
although the rate of metabolic reactions is lower in skeletal muscles , they account for around 20% of the total energy expenditure due to a 5060% contribution to a total body mass .
several micrornas were reported to control processes related to metabolism such as insulin secretion ( mir-9 , mir-375 ) , adipocyte differentiation ( mir-143 ) , fatty acid metabolism ( mir-122 ) , and myogenesis ( mir-1 , mir-133a , mir-133b , and mir-206 ) ( reviewed in ) .
of potential meaning is also mir-378a , located in the gene encoding master metabolic regulator , peroxisome proliferator - activated receptor gamma , coactivator 1 beta ( pgc-1 ) .
mir-378a was found to affect lipid and xenobiotic metabolism , lipid storage , mitochondrial function , and shift towards a glycolytic pathway ( warburg effect ) [ 5 , 6 ] .
because nutrients supply for metabolic processes is a matter of circulation , metabolically active tissues require high vascular density .
recently , mir-378a was reported to regulate tumor angiogenesis mainly via inhibition of tumor suppressors sufu and fus-1 [ 8 , 9 ] .
thus , a growing body of evidence suggests a role of mir-378a as a mediator controlling reciprocally dependent processes such as metabolism , muscle differentiation / regeneration , and angiogenesis .
micrornas ( mirnas ; mirs ) are small noncoding rna molecules with an average length of 21 - 22 nucleotides which can regulate gene expression posttranscriptionally by targeting mostly the 3untranslated region ( 3utr ) of mrnas .
however , mirna target sites were also found on the 5utr regions of human mrna . since their discovery in c. elegans in 1993 ,
mirnas currently can be recognized as potent players in wide spectrum of biological processes like development , differentiation , cellular defense mechanisms , and others .
conservative estimates state that over 30% of mrna expression is regulated by mirnas [ 12 , 13 ] .
however , others suggest that even up to 60% of the mrna expression is targeted by mirnas .
mirnas are often located in the introns of coding genes or noncoding sequences but can also be located in exons .
intronic mirnas can be expressed together with their host gene mrna being derived from a common rna transcript [ 15 , 16 ] .
other mirnas can also have their own promoters , which enable independent expression , or can be organized in clusters sharing a common transcriptional regulation [ 17 , 18 ] .
mirnas transcription is rna polymerase ii - dependent . in the case of mirnas that are encoded in their own genes , the primary mirna transcript ( pri - mirna )
is several kilobases long , while mirnas encoded in intronic regions of other genes ( mirtrons ) have shorter transcripts .
the mirna stem loop is excised from pri - mirna by endoribonuclease drosha / dgcr8 ( microprocessor complex ) and a hairpin called pre - mirna is exported from the nucleus by exportin-5 in a ran - gtp dependent manner . an endoribonuclease dicer removes the hairpin loop sequence from pre - mirna , creating a double stranded mirna duplex . depending on the relative stability of the mirna duplex , one or , more rarely , both strands can be incorporated in a multiprotein rna - induced silencing complex ( risc ) .
when there is perfect pairing between the mirna sequence and its target site , mrna is cleaved by a protein part of the risc called argonaute ( ago ) .
if the pairing is partial , deadenylation of the mrna via recruitment of the ccr4-not complex by the gw182 proteins inside the risc takes place and the poly - a tail is lost , leaving the mrna vulnerable to rnase activity , ubiquitination , and mrna degradation .
alternatively , mirna - induced risc can also cause repression of translation by mechanisms such as , for example , the promotion of ribosome drop - off from the mrna transcript or destabilization of the mrna binding cap protein ( figure 1 ) ( reviewed in [ 20 , 21 ] ) .
the pre - mir gives rise to a leading strand ( mir-378a-3p , previous ids for murine sequence : mmu - mir-422b , mmu - mir-378 , and mmu - mir-378 - 3p ; for human : hsa - mir-422b and hsa - mir-378 ) and a passenger strand ( mir-378a-5p , previous ids for murine sequence : mmu - mir-378 , mmu - mir-378 , and mmu - mir-378 - 5p ; for human : hsa - mir-378 and hsa - mir-378 ) .
mirna-378a-3p mature strand was first identified in 2004 in humans ( originally named mir-422b ) .
recently , other mirs with similar sequences but other localizations in the genome have been discovered and named : mmu - mir-378b , c , d in mouse and hsa - mir-378-b , c , d1,d2,e , f , g , h , i , j in human [ 2327 ] ( table 1 ) . in humans , mir-378a is by far the most expressed of the mir-378 sequences , with 7030 reads per million , in 78 experiments during deep sequencing , compared with 1013220 reads per million , in 4272 experiments for the other forms , respectively . in mice , mir-378a and mir-378b
have similar expression levels , at 11700 and 11000 reads per million ( mirbase , version 21 , september 2015 ) .
the sequence of mir-378a mature strands is highly conserved between species , with the mir-378a-5p strand being identical in both human and mice and the mir-378a-3p strand only differing in one nucleotide ( table 2 ) [ 6 , 27 ] .
pgc-1 may regulate several facets of energy metabolism such as mitochondrial biogenesis , thermogenesis , and glucose and fatty acid metabolism .
both strands of mir-378a are coexpressed with pgc-1 as shown , for example , in the liver and during adipocyte differentiation [ 6 , 29 ] .
the coexpression of mir-378a with its host gene implies they may share the same transcriptional activators , and mir-378a might be involved in similar processes as pgc-1. accordingly , high levels of ( porcine ) mir-378 - 1 ( table 2 ) expression are found in developing muscle , postnatal muscle , and myocardium and in brown adipose tissue [ 29 , 30 ] . to date
, only a limited number of mir-378a targets , which can be predicted based on in silico analysis , have been experimentally validated .
the latter , however , imply a role of mir-378a in mitochondrial energy homeostasis , glycolysis , and skeletal muscle development and in tumor angiogenesis and other processes ( table 3 ) .
a major source of energy production comprises oxidation of glucose in glycolysis followed by oxidation of pyruvate in well - oxygenated cells ( or followed by lactic acid fermentation in cancer , the warburg effect ) and from -oxidation of lipids , which yields even more atp per gram then carbohydrates metabolism .
a location of mir-378a in the gene encoding pgc-1   implies an involvement of mir-378a in metabolic pathways . unlike its homologue , pgc-1 , the expression of pgc-1
is not elevated in response to cold exposure   but occurs in response to hypoxia , exercise , caloric restriction , or aging ( reviewed in ) .
pgc-1 is preferentially expressed in tissues with relatively high mitochondrial content , such as heart , skeletal muscle , and brown adipose tissue . in 2002
, pgc-1 was first cloned and shown to be upregulated in the liver during fasting .
pgc-1 strongly activates hepatic nuclear factor 4 ( hnf4 ) and ppar , both of these nuclear receptors being important for the adaptation of hepatocytes to the effects of fasting .
these findings could hint to a possible role of pgc-1 in the regulation of gluconeogenesis and fatty acid oxidation in the liver .
pgc-1 is also involved in the regulation of energy expenditure or in the pathway of estrogen receptor - related receptors ( errs ) [ 3337 ] . since mirnas originating in the introns of host genes
may modulate the protein encoded by their parental genes and may be involved in the same mechanisms [ 3840 ] , mir-378a is proposed to be involved in the metabolic pathways affected by pgc-1 .
it was reported that mice lacking the first intron of the ppargc1b gene ( and thus mir-378a ) have a significantly higher oxygen capacity and mitochondrial function .
they identified a mediator complex subunit 13 ( med13 ) , involved in nuclear receptor signaling , and carnitine acetyltransferase ( crat ) , a mitochondrial enzyme involved in fatty acid metabolism , as targets of mir-378a-5p and mir-378a-3p , respectively .
regulated also cytochrome p450 2e1 ( cyp2e1 ) being involved in the metabolism of , for example , drugs and toxins . in addition , it has been discovered that transcription factor nuclear respiratory factor-1 ( nrf-1 ) , a critical regulator of the expression of some important metabolic genes in mitochondria regulating cellular growth , is inhibited by mir-378a-3p .
thus , mir-378a can be considered as a regulator of mitochondrial function in cells overexpressing mir-378a .
moreover , mir-378a-5p inhibits the mrnas of err and ga - binding protein- in breast cancer , which both interact with pgc-1 and together control oxidative metabolism .
this leads to a reduction of tricarboxylic acid gene expression and oxygen consumption and an increase in lactate production , which shifts cells from an oxidative towards a glycolytic pathway . in this way
, mir-378a-5p is believed to be a switch regulating the warburg effect in breast cancer .
moreover , in situ hybridization experiments in this study showed that mir-378a-5p expression correlates with progression of breast cancer .
the proposed regulating role of mir-378a-5p on the warburg effect is in parallel with the effects of pgc-1 , which mediates gluconeogenesis and fatty acid metabolism after periods of fasting or intense exercise .
coactivation by pgc-1 of err and ppar makes muscle fibers in pgc-1 transgenic mice more rich in mitochondria and highly oxidative . accordingly
increased glycolytic rates and increased cell proliferation can be related to lactate production by lactate dehydrogenase ( ldh ) .
ldha was found to be a direct target of mir-378a in the study of mallat et al . .
hsa - mir-378a-3p represses cell growth and increases cell death by targeting ldha . of note , hsa - mir-378a-3p and hsa - mir-378a-5p had opposite effects on ldha expression .
in addition , mir-378a is also considered as an important factor in adipogenesis and lipid storage .
there is a complex family of factors regulating those processes such as insulin , insulin - like growth factors ( igfs ) , glucagon , and thyroid hormones t3 and t4 ( reviewed in [ 4649 ] ) .
as mentioned before , it was demonstrated that mir-378a - knockout mice do not get fat after 8 weeks of high fat diet .
such animals show an enhanced mitochondrial fatty acid metabolism and have elevated oxidative capacity of tissues targeted by insulin ( e.g. , liver , muscles , and adipose tissues ) . in accordance with that , it was shown that mature strands of bta - mir-378 - 1 ( table 1 ) are expressed at higher level in cows with high ( versus low ) amount of back fat .
similarly , an inhibition of both mmu - mir-378a-3p and its host gene , pgc-1 , by the flavonoid fisetin lowered the accumulation of fat in the liver .
interestingly , mmu - mir-378a-5p was downregulated in mice that were fed a high fat diet for five months .
overexpression of mir-378a-3p/-5p during adipogenesis increased the transcriptional activity of ccaat / enhancer - binding proteins ( cebp ) alpha and beta , which can stimulate the expression of leptin , a hormone produced mainly by adipocytes which controls the homeostasis of body weight   ( reviewed in [ 52 , 53 ] ) . on the other hand , tnf- , il-6 , and
leptin are reported to increase the expression of mir-378a-3p in mature human adipocytes in vitro .
these cytokines are mainly secreted in the adipose tissue and are suggested to be involved in development of insulin resistance [ 55 , 56 ] . in addition , mir-378a-3p was shown to target insulin growth factor 1 receptor ( igf1r ) and reduce the akt signaling cascade in cardiomyocytes during cardiac development . moreover , in tissues where igf1 levels were high ( e.g. , fibroblasts and fetal hearts ) , mir-378 - 3p levels were very low , showing an inverse relation and suggesting a negative feedback loop between mir-378a-3p , igf1r , and igf1 .
the latter functions as a master regulator of adipogenesis and is involved in the formation of peroxisomes and the catabolism of very long chain fatty acids [ 58 , 59 ] .
accordingly , the amount of adipose tissue does not increase in mice lacking ppar when they are fed a high fat diet .
it was also reported that in cultured adipocytes mmu - mir-378a and pgc-1 expression is ppar , or rosiglitazone ( a ppar ligand ) , dependent , finding two peroxisome proliferator response elements in the mir-378a loci . on the other hand , overexpression of mir-378a elevated the expression of ppar isoform 2 , suggesting positive feedback loop and confirming the involvement of mir-378a in the storage of fat .
there are several activators known to induce expression of ppar such as the members of the e2f transcription factor family and prostaglandin j-2 ( pgj-2 ) [ 6365 ] .
the latter may act through rar - related orphan receptor alpha ( rora ) , which is frequently found in myocardium .
in addition to ppar , rora regulates also myod , a major transcription factor involved in skeletal muscle differentiation [ 67 , 68 ] .
interestingly , rora is a possible ( but not yet validated ) target for mir-378a-3p .
a proteomics - based study revealed several other proteins that are potentially targeted by rat mir-378a-3p or mir-378a-5p .
mir-378a-3p was shown to regulate mannose-1-phosphate guanylyltransferase ( gdp ) , dimethylarginine dimethylaminohydrolase 1 ( ddah1 ) , and lactate dehydrogenase a ( ldha ) ; all those proteins are participating in metabolic processes . on the other hand , tropomyosin beta chain , which is involved in the regulation of atpase activity ,
high levels of murine and rat mir-378a-3p , mir-378a-5p , and porcine mir-378 - 1 are reported in both developing and adult skeletal muscles [ 7 , 30 , 44 ] .
myod and myog play a role in the processes of myogenesis and muscle regeneration , in which dormant satellite cells are activated upon muscle damage and start proliferating and differentiating into muscle fibers ( reviewed in [ 70 , 71 ] ) .
it has been shown that mir-378a-3p targets the myogenic repressor myor during myoblast differentiation , which directly inhibits myod .
on the other hand , myod is upregulated in response to mir-378a-3p overexpression and , conversely , the level of mir-378a-3p may be enhanced by myod .
thus , there is evidence for a feedback loop in which mir-378a-3p regulates muscle differentiation via inhibiting myor , leading to an increase of myod , which in turn enhances mir-378a-3p .
that mir-378a may also control the development of skeletal muscle mass after training . in this study , mir-378a ( strand not specified ) was significantly downregulated in men who obtained low training - induced muscle mass gain compared to men who obtained high training - induced muscle mass gain .
mir-378a-3p is expressed mostly by cardiomyocytes , but not by nonmuscle cells , whereas the level of mir-378a-5p was reported to be very low in the heart .
fang et al . showed that mir-378 - 3p is significantly downregulated both in vitro in cardiomyocytes cell cultures exposed to hypoxia and in vivo during myocardial injury in rats .
overexpression of mir-378a-3p enhanced cell viability and inhibited apoptosis via caspase-3 inhibition . in contrast to this finding , another study found that mir-378a-3p downregulation enhanced the survival of cardiac stem cells via focal adhesion kinase activation and releasing connective tissue growth factor ( ctgf ) , the latter being a target of mir-378a-3p .
overexpression of mir-378a-3p in the study of knezevic et al . increased apoptosis of cardiomyocytes via the direct targeting of igf1r leading to a decrease of akt signaling .
this is in opposition to the previously mentioned study of fang et al . which showed apoptosis
the converse findings of the studies could be explained by different models used by knezevic et al . and
because of those discrepancies , the role of mir-378a in apoptosis of cardiomyocytes requires further investigation .
the finding that mir-378a-3p affects both igf1r and the akt pathway was confirmed   in a study which found that overexpression of mir-378a-3p in rhabdomyosarcoma suppressed igf1r expression and affected phosphorylation of the akt protein .
mir-378a-5p was shown to target heat shock protein 70.3 ( hsp70.3 ) in mouse hearts in normoxic conditions , but in hypoxic conditions a transcript variant of hsp70.3 without mir-378a-5p target site in its 3-utr is not repressed and can exert its cytoprotective properties .
mir-378a-3p prevented cardiac hypertrophy by targeting either ras signaling or the mitogen - activated protein kinase ( mapk ) pathway [ 77 , 78 ] .
more studies on the effect of mir-378a expression in muscle disorders would also be desirable . in both golden retriever muscular dystrophy dogs and duchenne muscular dystrophy patients ,
all in all , these findings suggest mir-378a-3p can be considered as an important player in cardiac development , remodeling , and hypertrophy .
angiogenesis comprises development of new blood vessels from existing ones , regulated by cytokines and growth factors such as , for example , vascular endothelial growth factor ( vegf ) , platelet - derived growth factor ( pdgf ) , and angiopoietin-1 ( ang-1 ) .
their expression can be posttranscriptionally controlled by micrornas such as mir-126 , mir-296 , mir-210 , mir-21 , and the mir-17~92 cluster   ( reviewed in ) .
skeletal muscles and heart muscle are tissues which , due to their oxygen and energy consumption , need to be sufficiently vascularized .
one of the major regulators of angiogenesis is the hypoxia - inducible factor-1 ( hif-1 ) , which controls over 100 genes   involved mainly in the glycolytic pathway and blood vessel formation , including vegf - a or interleukin-8 [ 8385 ] .
vegf is generally induced by hypoxia , while il-8 in at least some cancers and endothelial cells can be diminished by hif-1 via inhibition of c - myc and sp-1 transcription factors [ 86 , 87 ] .
c - myc , known as a regulator of cell cycle progression , apoptosis , and cellular transformation , is also a potent activator of pgc-1 and , in turn , mir-378a-3p , upregulating their expression .
in addition , mir-378a has been shown to affect vegf - a in two ways .
human hsa - mir-378a-5p ( by the study of hua et al . named as mir-378 ) can directly affect vegf - a by competing with hsa - mir-125a for the same seed - region in the vegf - a 3utr causing upregulation of vegf - a .
mir-378a-5p can also indirectly regulate vegf - a affecting sonic hedgehog ( shh ) signaling via sufu inhibition , which is an inhibitory component of this signaling pathway .
the shh pathway in turn can upregulate vegf - a and also other regulators of blood vessels formation , ang-1 and ang-2 expression [ 9092 ] .
increased expression of vegf - a , as well as pdgf and tgf1 , was also seen in mesenchymal stromal cells ( mscs ) transfected with rno - mir-378a-5p . in skeletal muscles , vegf - induced angiogenesis appears not to be regulated by the well - known hif pathway but by pgc-1 , which coactivates estrogen - related receptor alpha ( err- ) on binding sites in the promoter and the first intron of the vegf gene , inducing its expression .
this angiogenic pathway shows new roles for pgc-1 and err- , which are important regulators of mitochondrial activity in response to stimuli like exercise .
if there might be a role for pgc-1 in this pathway , it is yet to be examined .
it is noteworthy , however , that mir-378a-5p is known to affect the estrogen receptors by inhibiting err , another estrogen - related receptor .
a role for mir-378a in cell cycle regulation and stimulation of cell growth is also proposed . in human mammary epithelial and breast cancer cell lines
, mir-378a-3p can target the antiproliferative protein tob2 , which is a suppressor of cyclin d1 , which in turn is required for cell cycle g1-phase to s - phase progression .
whether mir-378 affects endothelial cell proliferation by regulation of cell cycle remains to be established .
the role of mir-378a in the formation of blood vessels nourishing tumor and enabling tumor growth was revealed .
mir-378a was found to be differentially regulated in different types of cancers   being downregulated in gastric cancer [ 96 , 97 ] , oral , and colon carcinoma , while being upregulated in renal   and lung cancer [ 9 , 101 ] . since it is also changed in serum or plasma of patients with prostate cancer , renal cancer [ 100 , 103 ] , and gastric cancer   and frequently found to be overexpressed in cryopreserved bone marrow mononuclear cells from acute myeloid leukemia patients , mir-378a might be considered as a biomarker .
the role of mir-378a in tumorigenesis , tumor growth , and tumor vascularization was revealed for the first time by lee and coworkers in glioblastoma .
they showed that mir-378a-5p enhances cell survival , reduces caspase-3 activity , and promotes tumor growth and angiogenesis , through repression of two tumor suppressors , sufu and fus-1 .
strikingly , nude mice injected with mir-378a-5p transfected cancer cells formed tumors of bigger volume and with larger blood vessels compared to gfp - transfected cells . on the other hand , high expression of mir-378a-5p in nsclc correlated with brain metastases due to higher cell migration , invasion , and tumor angiogenesis .
another study confirmed the downregulation of fus-1 by mir-378a-5p and showed that in the hepg2 liver cancer cells mir-378a-5p overexpression enhanced proliferation , migration , and , when injected in mice , invasion .
also in rhabdomyosarcoma , enhanced expression of mir-378a , vegf , and mmp9 correlated with increased vascularization and metastasis . taken together
, these studies suggest that mir-378a may serve as a prognostic marker in cancer due to its effects on angiogenesis .
our recent data confirmed the proangiogenic effect of mir-378a ( both strands ) in non - small cell lung carcinoma ( nsclc ) and pointed at its correlation with heme - degrading enzyme , heme oxygenase-1 ( ho-1 ) .
an involvement of ho-1 in angiogenesis and vegf - a as well as il-8 signaling was shown by us previously ; however , its action in tumors seems to be complex . in nci - h292 cell line overexpressing ho-1 , mir-378a ( both strands )
also overexpression of the mir-378a precursor sequence diminished ho-1 expression . conditioned medium from nci - h292 cells overexpressing mir-378a enhanced angiogenic potential of hmec-1 endothelial cell line .
tumors formed by such cells in subcutaneous xenografts showed enhanced growth , vascularization , oxygenation , and distal metastasis in vivo .
these interactions between mir-378a and ho-1 were confirmed in our studies on the role of the nrf-2 transcription factor / ho-1 axis in nsclc cell lines [ 110 , 111 ] . on the other hand ,
enhanced expression of mmu - mir-378a-5p in 4t1 murine breast cancer cells decreased the proliferation , migration , and invasiveness of these cancer cells in vitro and in vivo by targeting fibronectin , resulting in inhibition of tumor growth .
recent study showed that mir-378a may act as a biomarker for response to antiangiogenic treatment in ovarian cancer .
low expression of mir-378a was associated with longer progressive - free survival in patients with recurrent ovarian cancer treated with the antiangiogenic drug bevacizumab .
overexpression of the mir-378a precursor in ovarian cancer cells altered expression of genes associated with angiogenesis ( alcam , ehd1 , elk3 , and tln1 ) , apoptosis ( rpn2 , hipk3 ) , and cell cycle regulation ( swap-70 , lsm14a , and rdx ) .
high mir-378a ( strand not specified ) expression in renal carcinoma correlated with higher levels of endothelial surface marker cd34 in these tumors .
notably , a recent study suggested clinical relevance for mir-378a in metastatic colorectal cancer , in which enhanced mir-378a expression significantly improved the sensitivity to cetuximab treatment in these patients .
mir-378a-5p transfection of mscs has been shown to enhance their survival and angiogenic potential under hypoxic conditions in vitro .
in coculture with human umbilical vein endothelial cells ( huvecs ) , mir-378a-5p - transfected mscs formed a larger number of vascular branches on matrigel . in the mscs transfected with mir-378a-5p , the expression of bcl-2-associated x protein ( bax ) , which is an important proapoptotic regulator , was decreased , leading to a better survival .
it still has to be determined if the proangiogenic effect of mir-378a in vivo is confined to tumor angiogenesis , or if this effect is also present in physiological angiogenesis and regenerative neovascularization .
recently , it was reported that anti - mir-378a-5p enhances wound healing process by upregulating integrin beta-3 and vimentin .
it was reported that pgc-1 induces angiogenesis in skeletal muscle , enhancing the expression of vegf both in vitro and in vivo after ( transgenic ) overexpression .
accordingly , it was also found that vegfa is upregulated in c2c12 myoblast cell line with pgc-1 overexpression . however , after a pcr - based gene array of 84 known angiogenic factors and further rt - pcr of individual genes , they concluded that pgc-1 triggered an antiangiogenic program .
after inducing hind limb ischemia in pgc-1 overexpressing mice , an impaired reperfusion was noticed when compared to wild type littermates .
the role of inflammation in angiogenesis is studied the most in the context of cancer ( e.g. , reviewed in [ 119 , 120 ] ) but is certainly not limited to this pathology .
both lymphoid ( reviewed in [ 121 , 122 ] ) and myeloid ( reviewed in ) derived inflammatory cells affect angiogenesis in a stimulating or inhibitory manner .
the role of mir-378a in inflammatory cells was reported and its anti - inflammatory effect could be suggested .
nk cells exert potent cytotoxic effects when activated by type i ifn from the host once infected .
mir-378a was found to be downregulated in activated nk cells and further proved to target granzyme b. thus , ifn- activation decreases mir-378a expression and in turn augments nk cell cytotoxicity .
accordingly , suppression of mir-378 targeting granzyme b in nk cells resulted in inhibition of dengue virus replication in vivo .
macrophages are known to play either inhibitory or stimulatory roles in angiogenesis ( reviewed by ) .
mirnas have been proposed to regulate activation and polarization of macrophages ( reviewed by [ 127 , 128 ] ) . in a study of rckerl
mir-378a-3p was identified as a part of the il-4-driven activation program of anti - inflammatory macrophages ( m2 ) .
mir-378a-3p was highly upregulated after stimulation with il-4 of peritoneal exudate cells of mice injected with the parasite brugia malayi compared to controls and infected il-4-knockout mice .
the study identified several targets for mir-378a-3p within the pi3  k / akt signaling pathway , which are important for proliferation but only partially responsible for m2 phenotype .
another study found mir-378a ( strand not specified ) expression upregulated after stimulation with cytokines like , for example , tnf- and il-6 . in line with its potential role in macrophages ,
mmu - mir-378a ( strand not specified ) has been found to be upregulated during osteoclastogenesis in vitro .
furthermore , serum levels of mir-378a-3p have been shown to correlate with bone metastasis burden in mice injected with mouse mammary tumor cell lines 4t1 and 4t1.2 .
a growing body of evidence suggests a role for mir-378a as a mediator controlling reciprocally dependent processes in metabolism , muscle differentiation / regeneration , and angiogenesis .
as mir-378a was found to be differentially regulated in different types of cancers and its level is changed in serum of prostate , renal , and gastric cancer patients , it can be considered as a biomarker for those diseases . the correlation between mir-378a expression and disease progression in lung cancer , liver cancer , and rhabdomyosarcoma suggests a further role of this microrna as a prognostic marker .
if more research will be done to the mechanisms of action , possibilities for therapeutic use of mir-378a could be sought in the field of metabolic disorders , obesity , or tumors .
more studies on the effect of mir-378a expression in muscle disorders would also be desirable .
the proangiogenic effect of mir-378a was observed in tumors ; however , no studies have been performed on the angiogenic effects of mir-378a in physiological settings or diseases where angiogenesis plays important roles , such as diabetes and cardiovascular diseases .
more study has to be done to assess the mechanisms of mir-378a function in blood vessel formation . of note , in contrast with proangiogenic role of mir-378a , inhibition of mir-378a-5p enhanced wound healing process .
this might suggest a role for mir-378a-5p in diseases such as diabetes or in decubitus ulcers , in which wound healing is impaired . of note is
the confusion that has arises because of a disarray in nomenclature with studies describing the same molecule , mir-378a , as mir-422b , mir-378 , or mir-378 .
in addition , it is not always clear which of the two mature strands of mir-378a is studied
. this could lead to misunderstandings and errors in interpreting the data published so far .
 microrna-378a ( mir-378a , previously known as mir-378 ) is one of the small noncoding rna molecules able to regulate gene expression at posttranscriptional level . 
 its two mature strands , mir-378a-3p and mir-378a-5p , originate from the first intron of the peroxisome proliferator - activated receptor gamma , coactivator 1 beta ( ppargc1b ) gene encoding pgc-1. embedding in the sequence of this transcriptional regulator of oxidative energy metabolism implies involvement of mir-378a in metabolic pathways , mitochondrial energy homeostasis , and related biological processes such as muscle development , differentiation , and regeneration . on the other hand , 
 modulating the expression of proangiogenic factors such as vascular endothelial growth factor , angiopoietin-1 , or interleukin-8 , influencing inflammatory reaction , and affecting tumor suppressors , such as sufu and fus-1 , mir-378a is considered as a part of an angiogenic network in tumors . in the latter 
 , mir-378a can evoke broader actions by enhancing cell survival , reducing apoptosis , and promoting cell migration and invasion . 
 this review describes the current knowledge on mir-378a linking oxidative / lipid metabolism , muscle biology , and blood vessel formation . 