inflammation represents a complex , nonspecific immune response of the body to pathogens , damaged cells , tissue injury , allergens , toxic compounds , or irritant molecules .
it may also escape the original tissue and spread via the circulatory and/or the lymphatic system to other parts of the body , producing a systemic inflammatory response syndrome such as sepsis in case of an infection .
chronic inflammation is associated with a simultaneous destruction and healing of the tissue from the inflammatory process and has been linked to a number of pathologies , including cancer , chronic asthma , rheumatoid arthritis , multiple sclerosis , inflammatory bowel diseases , and psoriasis , as well as several types of neurological disorders .
the inflammatory response is coordinated by a large range of mediators that form complex regulatory networks .
it is mediated by several types of chemokines [ 13 ] , which act through their receptors located at the surface of the cytoplasmic membrane of leukocytes .
the production of chemokines is induced by inflammatory stimuli such as bacterial lipopolysaccharide ( lps ) , interleukin ( il)-1 , or tumor necrosis factor ( tnf ) .
finely tuned molecular mechanisms exist that ensure that the immune response required for the defense of the body has a limited duration and does not pass a certain maximum activation level , thus avoiding that , it becomes harmful to the organism .
epidemiological studies suggest that as many as 25% of all cancers may be due to chronic inflammation [ 57 ] .
the connection between inflammation and cancer consists of an extrinsic pathway , driven by inflammatory conditions that increase cancer risk , and an intrinsic pathway , driven by genetic alterations that cause inflammation and neoplasia .
inflammatory mediators released by cancer - related inflammation induce genetic instability , leading to the accumulation of random genetic alterations in cancer cells .
the activation of toll - like receptors ( tlrs ) , a group of pattern recognition receptors functioning as sensors of pathogens and tissue damages , leads to the nuclear translocation of nf-b and the production of cytokines such as tnf , il-1 , il-1 , il-6 , and il-8 .
however , tlr activation has been shown to accelerate the growth of adoptively transferred tumors [ 811 ] .
accordingly , the stimulation of tlrs leads to increased survival and proliferation of several cell lines [ 12 , 13 ] , and the intratumoral injection of listeria monocytogenes induces tlr2 signaling in tumor cells , thus promoting their growth .
chemokines also affect several tumor progression pathways , such as leukocyte recruitment and function , cellular proliferation , survival , or senescence , as well as invasion and metastasis and are the targets of a number of anticancer agents .
tumor microenvironment contains various inflammatory cell types infiltrating the tumor area in response to inflammatory stimuli , such as macrophages , neutrophils , and mast cells [ 16 , 17 ] .
tumor - associated macrophages ( tams ) are thought to play key roles in the production of various growth factors , angiogenic factors , proteinases , chemokines , and cytokines , through crosstalks with cancer cells and other tumor stromal cells [ 1820 ] .
factors secreted by tams stimulate cell migration / motility , proliferation , survival , angiogenesis , and metastasis , resulting in a dynamic environment that favors the progression of cancer , thus affecting the clinical outcome of malignant tumors .
tams have thus been described as  obligate partners for tumor - cell migration , invasion and metastasis  [ 21 , 22 ] .
namely , in a genetic model of breast cancer in macrophage - deficient mice , the tumors developed normally but were unable to form pulmonary metastases in the absence of macrophages . as tumor metastasis is responsible for approximately 90% of all cancer - related deaths , a better understanding of inflammation regulatory mechanisms may potentially allow to optimize the use of anticancer drugs that lower tumor - specific inflammatory response . finally , the transforming growth factor  ( tgf ) regulates the immune response as well as the effects of the immune system on tumor progression or regression in vivo .
tgf has been shown to suppress the antitumor activity of t cells , natural killer ( nk ) cells , neutrophils , monocytes , and macrophages , which together are able to promote or repress tumor progression depending on the cellular context [ 2527 ] .
importantly , tgf1 , the most abundant and ubiquitously expressed isoform of tgf , is usually considered a tumor - suppressor , due to its cytostatic activity in epithelia . however , on advanced stages of tumors , tgf1 behaves as a tumor promoter , due to its capability to enhance angiogenesis , epithelial - to - mesenchymal transition , cell motility , and metastasis [ 2830 ] .
micrornas ( mirnas ) are short noncoding rnas which regulate the translation and/or degradation of target messenger rnas [ 3133 ] .
they have been implicated in the regulation of a number of fundamental processes , including muscle , cardiac , neural , and lymphocyte development , or the regulation of both the innate and adaptative immune responses [ 34 , 35 ] .
mirnas originate from primary transcripts ( pri - mirnas ) converted in the nucleus into precursor mirnas ( pre - mirnas ) by the rnase iii drosha , associated with dgcr8 to form the small microprocessor complex .
pre - mirnas are then exported in the cytoplasm where the mirna hairpin is cleaved by the rnase iii dicer within the risc loading complex .
the guide strand , which corresponds to the mature mirna , is then incorporated into the risc complex .
mirnas and their transcriptional regulators usually form autoregulatory loops aimed at controlling their respective levels .
mirnas participate in many gene regulatory networks whose molecular malfunctions are associated with major pathologies such as cancer   or auto - mmune diseases [ 3840 ] .
thus the expression of mir-155 is strongly elevated in several human leukemias and lymphomas ( and references therein ) .
transgenic mice with b cells overexpressing mir-155 develop b - cell leukemia , and a sustained expression of mir-155 in hematopoietic stem cells causes a myeloproliferative disorder . on the other side ,
mir-155 has been implicated in the regulation of myelopoiesis and erythropoiesis , th1 differentiation , b - cell maturation , igg1 production , somatic hypermutations , gene conversion , class switch recombination , and b- and t - cell homeostasis as well as in the regulation of the innate immune response .
thus , mir-155 levels increase following lps treatment of raw-264 macrophages , and mir-155 transgenic mice show enhanced sensibility to lps - induced endotoxin shock . in contrast , mir-155-knock - out mice are unable to mount a proper t - cell or b - cell immune response .
the expression of another mirna , mir-125b , was repressed within 1 hour of lps challenge in raw-264 cells . in topic eczema
, mir-125b expression was reduced in regions of the skin that were inflamed , while that of mir-21 was enhanced .
similarly , mir-21 expression was increased by inflammation due to ulcerative colitis   and also by il-13 and by specific antigens in ova- and aspergillus fumigatus antigens - induced asthma models .
the expression of mir-21 changes dynamically during antigen - induced t - cell differentiation , with the highest levels of expression in the effector t cell . mir-21 induction upon t - cell receptor ( tcr ) stimulation is believed to be involved in a negative feedback loop regulating tcr signaling .
mir-663 has drown recent attention due to its role not only as an anti - inflammatory mirna but also as a tumor suppressor mirna .
in addition , the expression of this microrna is lost in certain cancers such as gastric or pancreatic cancer , and it induces mitotic catastrophe growth arrest when its expression is restored in these cells .
mirnas participate in many gene regulatory networks whose molecular malfunctions are associated with cancers [ 35 , 41 ] . depending on the effects of their downregulation or overexpression , mirnas have been described either as oncogenic ( onco - mirs ) or tumor suppressors .
thus , the mir-17 - 92 cluster on chromosome 13 , which contains six mirnas ( mir-17 , -18a , -19a , -20a , -19b-1 , and -92a-1 ) , is amplified and overexpressed in b - cell lymphomas and solid tumors such as breast or small - cell lung cancers , where it may enhance oncogenesis by potentially targeting e2f1 , p21/cdkn1a , and bcl2l11/bim . on the other hand , loss of function of mir-17 - 92 mirnas might be advantageous for cancer cells in certain settings .
namely , loss of heterozygosity at the 13q31.3 locus has been observed in multiple tumor types , and a genome - wide analysis of copy number alterations in cancer revealed that the mir-17 - 92 cluster was deleted in 16.5% of ovarian cancers , 21.9% of breast cancers , and 20% of melanomas .
in contrast , the twelve members of the human let-7 gene family are frequently downregulated in cancers like lung , colon , or other solid tumors [ 34 , 35]s and are , therefore , s considered as tumor - suppressor mirnas in these types of cancers .
in particular , let-7 mirnas target oncogenes of the ras family   and c - myc , and their expression in colon tumors results in reduced levels of both ras and c - myc .
mir-21 is overexpressed in several cancers , including colorectal carcinomas ( crcs ) , gliomas , as well as breast , gastric , prostate , pancreas , lung , thyroid , and cervical cancers [ 53 , 54 ] .
mir-21 has been shown to function as an onco - mir , due to its targeting of transcripts encoding key regulators of cell proliferation and apoptosis such as pten and pdcd4 . beside mir-21
, several mirnas are overexpressed in crcs , including mir-17 , mir-25 , mir-26a , and mir-181a [ 54 , 55 ] .   in human ,
the levels of both mir-155 and bic transcripts ( that is , mir-155 primary rnas ) are elevated in diffuse large b - cell lymphoma ( dlbcl ) , hodgkins lymphoma , and primary mediastinal b - cell lymphoma .
in contrast , a very weak expression of mir-155 is found in most non - hodgkins lymphoma subtypes , including burkitt lymphoma . in addition
, high levels of bic and mir-155 expression were reported in b - cell chronic lymphocytic leukemia ( b - cll ) and in b - cll proliferation centers .
furthermore , mir-155 was also upregulated in a subset of patients with acute myelomonocytic leukemia and acute monocytic leukemia . accordingly ,
transgenic mice whose b cells overexpress mir-155 developed polyclonal preleukemic pre - b - cell proliferation followed by b - cell malignancy . on the other hand , it was reported that bic cooperates with c - myc in avian lymphomagenesis and erythroleukemogenesis . beside liquid malignancies ,
high levels of mir-155 expression were found in solid tumors such as breast , colon , and lung cancers .
mir-155 was recently shown to induce a mutator phenotype by targeting wee-1 , a kinase regulating g2/m phase transition during the cell cycle .
furthermore , it was shown that mir-155 increases genomic instability by targeting transcripts encoding components of the dna mismatch repair machinery . as a consequence ,
the simultaneous mir-155-steered suppression of a number of tumor suppressor genes combined with a mutator phenotype might allow the shortening of steps required for tumorogenesis , and might also explain how chronic inflammation associated with high levels of mir-155 induces cancer .
for example , it has been established that the downregulation of both mir-103 - 1 and mir-103 - 2 mirnas induces epithelial - to - mesenchymal transition by targeting dicer1 transcripts .
furthermore , several mirnas , including mir-21 , have been shown to activate metastasis by acting on multiple signaling pathways and targeting various proteins that are involved in this process .
thus , in breast cancer , which represents the most common malignancy among women in the world , mirnas such as mir-9 , mir-10b , mir-21 , mir-103/107 , mir-132 , mir-373 , and mir-520 stimulate metastasis , while mir-7 , mir-30 , mir-31 , mir-126 , mir-145 , mir-146 , mir-200 , mir-205 , mir-335 , mir-661 , and mirnas of the let-7 families in contrast impair the different steps of metastatic process , from epithelial - to - mesenchymal transition to local invasion to colonisation and angiogenesis .
numerous reports have provided strong evidence that all of the above mirnas potentially target a myriad of transcripts including those encoding transcription factors , cytokines , enzymes and kinases , implicated in both cancer and inflammation .
resveratrol ( trans-3,4,5-trihydroxystilbene ) is a natural polyphenolic , nonflavonoid antioxidant found in grapes and other berries , produced by plants in response to infection by the pathogen botrytis cinerea .
recent studies have documented that resveratrol has various health benefits , such as cardiovascular- and cancer - preventive properties [ 6365 ] , and this compound is currently at the stage of preclinical studies for human cancer prevention [ 66 , 67 ] .
resveratrol was first shown to inhibit both tumor promotion and tumor progression in a mouse skin cancer model .
resveratrol is also tested for preventing and/or treating obesity and diabetes [ 69 , 70 ] .
fortunately , resveratrol toxicity is minimal , and even proliferating tissues such as bone marrow or intestinal tract are not adversely affected .
both its m - hydroxyquinone and 4-hydroxystyryl moieties have been shown to be important for the determination of resveratrol inhibitory properties toward various enzymes .
this include lipoxygenases and cyclooxygenases that synthesize proinflammatory mediators from arachidonic acid , protein kinases such as pkcs and pkd , and receptor tyrosine kinases , lipid kinases , as well as ikk , an activator of nf-b pathway , which establishes a strong link between inflammation and tumorigenesis .
also , resveratrol inhibition of p450/cyp19a1/aromatase , by limiting the amount of available estrogens and consequently the activity of estrogen receptors , has been proposed to contribute to the protection against several types of cancer , including breast cancer [ 72 , 73 ] . of note
, resveratrol also inhibits the formation of estrogen - dna adducts , which are elevated in women at high risk for breast cancer .
it induces growth arrest followed by apoptotic cell death and interferes with cell survival by upregulating the expression of proapoptotic genes while simultaneously downregulating the expression of antiapoptotic genes .
resveratrol induces the redistribution of cd95 and other death receptors in lipid rafts , thus contributing to their sensitization to death receptor agonists .
it also causes growth arrest at g1 and g1/s phases of cell cycle by inducing the expression of cdk inhibitors p21/cdkn1a and p27/cdkn1b .
in addition , resveratrol directly inhibits dna synthesis by diminishing ribonucleotide reductase and dna polymerase [ 72 , 76 , 77 ] . altogether , antiproliferative activities of resveratrol involve the differential regulation of multiple cell - cycle targets in a cell - type - dependent manner [ 72 , 75 ] .
one of the possible mechanisms for resveratrol protective activities is by downregulation of the inflammatory responses . that includes the inhibition of synthesis and release of proinflammatory mediators , modifications of eicosanoid synthesis , or inhibiting the enzymes , such as cyclooxygenase-1 ( cox-1/ptgs1 ) or -2 ( cox-2/ptgs2 ) , which are responsible for the synthesis of proinflammatory mediators , through the inhibitory effect of resveratrol on transcription factors like nf-b or activator protein-1 ( ap-1 ) [ 78 , 79 ] . of note
, constitutive cox-2 expression generally predicts aggressiveness of tumors , therefore , the use of nonsteroidal anti - inflammatory drugs that inhibit cox-2 in cancer treatment .
this nuclear relocalization of cox-2 is induced by resveratrol , and exposure of resveratrol - treated cells to a specific cox-2 inhibitor blocked resveratrol - induced apoptosis , indicating that cox-2 displays proapoptotic activity in the nucleus , which may be associated with the generation of complexes of cox-2 and erk1/2 mitogen - activated protein kinases . in mouse macrophages
, resveratrol also displays antioxidant activity , decreasing the production of reactive oxygen species and reactive nitrogen species and inhibiting nitric oxygen synthetase ( nos)-2 and cox-2 synthesis as well as prostaglandin e2 production .
furthermore , in 3t3-l1 adipocytes , resveratrol inhibits the production of the tnf - induced monocyte chemoattractant protein ( mcp)-1/ccl2 .
mcp-1 plays an essential role in the early events during macrophage infiltration into adipose - tissue , which results in chronic low - grade inflammation , a key feature of obesity type 2 diabetes characterized by adipose tissue macrophage infiltration and abnormal cytokine production .
finally , it is also well established that some anti - inflammatory effects of resveratrol arise from its capability to upregulate histone deacetylase sirtuin 1 ( sirt1 ) activity , that also presents antitumor and anti - inflammatory capabilities .
altogether , it is clear that the key antitumor properties of resveratrol [ 7782 ] are linked to its anti - inflammatory effects .
the fact that resveratrol targets , directly or indirectly , so many different factors , exerts such a wide influence on cell homeostasis , and provides such a range of health benefits , suggested that some of its effects should arise from its capability to modulate the activity of global regulators .
furthermore , the ability of each mirna to potentially regulate the levels and , therefore , the activity , of tens to hundreds of target genes , strongly suggested that resveratrol should be able to modify the composition of mirna populations .
indeed , it has recently been shown that resveratrol decreases the levels of several proinflammatory and/or oncogenic mirnas and upregulates mirnas with anti - inflammatory and/or antitumor potentials [ 47 , 83 ] .
affymetrix microarrays and rnase - protection assays showed that resveratrol treatment of human thp-1 monocytic cells upregulated the expression of loc284801 transcripts , that contain the sequence of pre - mir-663 and thus represent mir-663 primary transcripts .
interestingly , in silico analysis using targetscan ( http://www.targetscan.org/ ) suggested that mir-663 may potentially target transcripts encoding factors implicated in ( i ) the mounting of the immune response , especially junb , jund , and fosb , which encode ap-1 factors known to activate many cytokine genes in partnership with nfat factors , ( ii ) tlr signaling , such as the kinases ripk1 and irak2 , and ( iii ) the differentiation of monocytes , th1 lymphocytes , and granulocytes .
an antisense mir-663 inhibitory rna ( 663-i ) proved capable of increasing global ap-1 activity in unchallenged thp-1 cells , showing that mir-663 indeed target transcripts encoding ap-1 factors in these cells .
these effects were in particular directed toward junb and jund transcripts . in agreement with previous results
, resveratrol blocked the surge of ap-1 activity that occurs following lps challenge due to the fact that junb transcripts peak within the first hour , leading to the accumulation of junb in the next few hours .
this inhibitory effect of resveratrol on ap-1 activity was partly impaired by 663-i , indicating that it arises at least in part from the upregulation of mir-663 by resveratrol .
western blots showed that resveratrol impaired junb neosynthesis , while still allowing the phosphorylation , that is , the activation of junb following lps treatment to take place , at least to a certain extent . given that ap-1 factors include c - jun , junb , jund , fosb , fra-1 , and fra-2 , as well as jun dimerization partners jdp1 and jdp2 or the closely related atf2 , lrf1/atf3 , and b - atf , so that potentially about 18 different dimeric combinations may be formed , the capability of resveratrol to specifically target a subset of ap-1 dimers through the upregulation of mir-663 might have profound effects on the levels of the transcriptional activity of promoters to whom different ap-1 factors can compete for binding .
due to the many roles of ap-1 factors both in inflammation and cancer [ 86 , 87 ] , the specific targeting of genes encoding a subset of ap-1 factors , by changing the composition of ap-1 dimers on key promoters , may possibly explain some of the multiple anti - inflammatory and anticancer properties of resveratrol . of note
accordingly , mir-663 reduced the upregulation of mir-155 by lps , which may be due to mir-663 targeting of transcripts encoding junb and jund and also possibly fosb and ksrp , an rna binding protein implicated in the lps - induced mir-155 maturation from its primary transcripts bic .
this is of primary importance , for mir-155 upregulation is the hallmark of inflammatory response following lps treatment of macrophages / monocytes .
resveratrol also dramatically impaired the upregulation of mir-155 by lps , an effect partly inhibited by 663-i .
altogether , these results indicate that the anti - inflammatory properties of resveratrol arise , at least in part , from its upregulation of mir-663 and its downregulating effects on mir-155 and that mir-663 might possibly qualify as an anti - inflammatory mirna .
the results reported here above also suggested that , due to its targeting of ap-1 factors , known to play a role in tumorigenesis and cell invasion [ 86 , 87 ] and due to its downregulation of mir-155 , whose levels increase in solid as well as in liquid tumors , mir-663 may also possibly provide resveratrol with some of its anticancer properties .
namely , mir-663 was found to be downregulated in hormone refractory prostate cancer cells , along with mir-146a and mir-146b , further supporting the hypothesis that this mirna is a tumor - suppressor gene whose one of the function is to keep low the expression level of oncogenic mir-155 [ 47 , 48 ] .
crc is the third most common malignancy and the fourth biggest cause of cancer mortality worldwide [ 91 , 92 ] . despite the increased use of screening strategies such as fecal occult blood testing , sigmoidoscopy , and colonoscopy , more than one - third of patients with colorectal cancer
will ultimately develop metastatic disease . on the other hand , the tgf signaling pathway is one of the most commonly altered cellular signaling pathways in human cancers . among the three tgf isoforms expressed in mammalian epithelia ( tgf1 , tgf2 , and tgf3 ) ,
tgf signaling is initiated by the binding of tgf ligands to type ii receptors ( tgfr2 ) .
once bound by tgf , tgfr2 recruits , phosphorylates , and thus activates the type i tgf receptor ( tgfr1 ) .
tgfr1 then phosphorylates two transcriptional regulators , namely , smad2 and smad3 , which subsequently bind to smad4 .
this results in the nuclear translocation of smad complexes , allowing smads to interact with transcription factors controlling the expression of a multitude of tgf responsive genes .
the expression of tgf1 in both tumor and plasma was found to be significantly higher in patients with metastatic colorectal cancer , and increasing colorectal tumor stage was correlated with higher tgf1 expression in tumor tissues .
mirna microarrays recently showed that resveratrol treatment of sw480 human colon cancer cells significantly increased the levels of 22 mirnas while decreasing those of 26 others . among the mirnas downregulated by resveratrol , mir-17 , mir-21 , mir-25 , mir-92a-2 , mir-103 - 1 and mir-103 - 2
have been shown to behave as onco - mirnas , at least in certain contexts .
thus , genomic amplification and overexpression of mir-17 - 92 mirnas is found in b - cell lymphomas as well as in breast and lung cancers [ 34 , 54 ] .
mir-21 is overexpressed in several cancers , including crcs , gliomas , as well as breast , gastric , prostate , pancreas , lung , thyroid , and cervical cancers [ 5355 ] .
mir-17 , mir-25 , mir-26-a , and mir-181a are also overexpressed in crcs [ 34 , 54 ] .
in addition , several mirnas , including mir-21 , have been shown to activate metastasis by acting on multiple signaling pathways and targeting various proteins that are key players in this process .
furthermore , the lower metastatic propensity of sw480 cells as compared with sw620 human colon cancer cells , both derived from the primary tumor and a metastasis of the same patient , respectively , was associated with a lower level of expression of mir-103 - 1 and mir-103 - 2 , two mirnas that induce epithelial - to - mesenchymal transition by targeting dicer1 transcripts . 
 in silico analysis using targetscan showed that mirnas downregulated by resveratrol in sw480 cells potentially target transcripts encoding known tumor suppressor factors , such as the two antiproliferation factors pdcd4 and pten , the components of the mismatch repair machinery mlh3 , msh2 and msh3 , dicer1 , the rnase iii producing mature mirnas from their immediate precursors in the cytoplasm , and several effectors and regulators of the tgf signaling pathway .
indeed , resveratrol treatment of sw480 cells lead to a greater accumulation of tgfr1 , tgfr2 , pdcd4 , pten , and e - cadherin ( a component of adherens junctions implicated in the maintenance of epithelial phenotype ) . of note , among mirnas upregulated by resveratrol , mir-663 was the only one to target tgf1 transcripts .
luciferase assays and western blots showed that resveratrol downregulated tgf1 in both a mir-663-dependent and a mir-663-independent manner .
resveratrol treatment also decreased the transcriptional activity of smads under tgf1 signaling , an effect seemingly independent of mir-663 .
interestingly , it has been recently shown that gam / znf512b , a vertebrate - specific developmental regulator first described in chicken , impairs the upregulation of mirnas of the mir-17 - 92 cluster by tgf1 and that tgf1 in turn downregulates gam , at least in part through the upregulation of mir-17 - 92 mirnas .
the facts that gam transcripts contain three consensus target sites for mir-663 and that gam is sensible to resveratrol treatment ( tili et al .
, unpublished results ) raises the question of the possible existence of a gene regulatory network that would allow mir-663 to impair gam repressing activity on tgf1 signaling pathway when tgf1 works as a tumor suppressor , that is , at the early stages of tumorigenesis but not any more when this pathway starts to favor tumorigenesis and metastasis , that is , on advanced stages of cancers .
it is important to emphasize that tgf1 has been shown to enhance the maturation of oncogenic mir-21 through the binding of smad3 to mir-21 primary rnas   and also to increase the expression of mir-155 , which is under the control of tgf/smad activity .
thus , by targeting ap-1 factors as well as tgf1 and possibly smad3 , mir-663 might inhibit two of the pathways that upregulate mir-155 expression .   the tgf signaling pathway present multiple levels of regulation : sequestration of ligands into inactive precursor forms , ligand traps , decoy receptors , and inhibitory smads , not to mention the existence of smad - independent pathways and their interactions with many other critical signaling pathways which also proved to play a role in cancer
it is thus not surprising that the short ( 307-nt long ) 3-utr of tgf1 transcripts contains a potential consensus target site for 28 mirnas only . of note ,
tgf1 3-utr contains two target sites for two of these mirnas and only one target site for 25 of the others .
therefore , the fact that mir-663 may potentially target 5 different sites in tgf1 3-utr suggests that this mirna could represent a critical tgf1 regulator which may possibly be called upon action in emergency situations such as those when cells begin to proliferate anarchically or when a stronger immune response is required .
the multiplicity of mir-663 targets sites in tgf1 3-utr further suggests that the effects of this mirna might be both dose- and context - dependent , so that resveratrol effects on tgf1 signaling pathway might well be also context - dependent . finally , it is probable that , depending on the cell context , resveratrol might either increase the level of tgf signaling  by inhibiting mirnas targeting its main effectors  when it is beneficial to the organism , that is , when it works to maintain the integrity of epithelia and impair cell proliferation , or in contrast decrease tgf1 signaling  by decreasing its production through the upregulation of mir-663when tgf1 starts to favor epithelial - to - mesenchymal transition and metastasis .
for example , the targeting of both tgf1 and smad3 transcripts might possibly allow resveratrol to impair tgf1-induced smad3-dependent promotion of cell motility and invasiveness in advanced stages of gastric cancer [ 101 , 102 ] or when smad2 and smad3 phosphorylated at both linker and cooh - terminal regions transmit malignant tgf1 signal in later stages of human crc .
it is notable that striking phenotypes are often driven through small changes in the cellular concentration of key factors . for example , in the b - cell compartment , mir-150 curtails the activity of c - myb transcription factor in a dose - dependent fashion over a narrow range of mirna and c - myb concentrations .
thus , even slight effects of resveratrol on a handful of key mirnas might well prove to be critical to its anti - inflammatory , anticancer and antimetastatic properties .
in addition , the fact that mir-663 , mir-21 , mir-155 , and tgf1 have all been implicated in the regulation of cell proliferation , tumor apparition and development , metastasis formation , and innate immunity , strongly suggests that the capability of resveratrol to behave at the same time as an antitumor , antimetastatic , antiproliferation and anti - inflammatory agent most probably arises from its effects on the expression of a small set of critical endogenous mirnas having the abilities to impact the cell proteome globally .
finally , mirnas have the promise to become biomarkers for different stages of cancer , both for diagnosis and prognosis .
furthermore , the discovery that resveratrol can modulate the levels of mirnas targeting proinflammatory and/or protumor factors opens the possibility to optimize resveratrol treatments by manipulating in parallel the levels of expression of a few critical mirnas .
for example , from the experiments reported here above , it starts to become clear that the use of resveratrol would be especially beneficiary in the type of cancers where the tgf pathway is implicated .
of course , resveratrol use would have to be carefully correlated with the stages of cancers , knowing that tgf can have two faces , that is , anti- and prometastatic . as a last remark ,
it should be noted that while resveratrol antitumor potential has been linked with data primarily from human cell culture systems , evidence that resveratrol can inhibit carcinogenesis in several organ sites emerged from results of cancer prevention and therapy studies in laboratory animal models . given that mir-663
[ 47 , 83 ] come as a warning that studies in animal may not always allow to predict accurately the molecular effects of resveratrol in human , especially when it comes to mirnas .
 micrornas are short noncoding rnas that regulate the expression of many target genes posttranscriptionally and are thus implicated in a wide array of cellular and developmental processes . 
 the expression of mir-155 or mir-21 is upregulated during the course of the inflammatory response , but these micrornas are also considered oncogenes due to their upregulation of expression in several types of tumors . 
 furthermore , it is now well established that inflammation is associated with the induction or the aggravation of nearly 25% of cancers . 
 therefore , the above micrornas are thought to link inflammation and cancer . 
 recently , resveratrol ( trans-3,4,5-trihydroxystilbene ) , a natural polyphenol with antioxidant , anti - inflammatory , and anticancer properties , currently at the stage of preclinical studies for human cancer prevention , has been shown to induce the expression of mir-663 , a tumor - suppressor and anti - inflammatory microrna , while downregulating mir-155 and mir-21 . in this paper 
 we will discuss how the use of resveratrol in therapeutics may benefit from the preanalyses on the status of expression of mir-155 or mir-21 as well as of tgf1 . 
 in addition , we will discuss how resveratrol activity might possibly be enhanced by simultaneously manipulating the levels of its key target micrornas , such as mir-663 . 
1. Inflammation and Cancer
2. MicroRNAs and Inflammation
3. MicroRNAs as Oncogenes and Tumor-Suppressor Genes
4. Anti-Inflammatory and Antitumor Properties of Resveratrol
5. 
6. MicroRNAs as Mediators of Resveratrol Anticancer Effects
7. Conclusions