Table Of ContentSunetal.JournalofHematology&Oncology2013,6:6
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JOURNAL OF HEMATOLOGY
& ONCOLOGY
REVIEW Open Access
Diverse functions of miR-125 family in different
cell contexts
Yu-Meng Sun1,2, Kang-Yu Lin1 and Yue-Qin Chen1*
Abstract
MicroRNAs (miRNAs) are emerging as a novel class of non-coding RNA molecules that regulate gene expression at
a post-transcriptional level. More than 1000 miRNAs have been identifiedin human cellsto date, and they are
reported to play important rolesin normal cell homeostasis, cell metastasis and disease pathogensis and
progression. MiR-125, which is a highly conserved miRNA throughout diverse speciesfrom nematode to humans,
consists ofthreehomologs hsa-miR-125a, hsa-miR-125b-1 and hsa-miR-125-2.Members of this family have been
validated to be down-regulated,exhibiting its disease-suppressing propertiesinmany different types of diseases,
whiletheyalso have disease-promotingfunctionsin certain contexts. MiR-125 targets a numberof genes such as
transcription factors, matrix-metalloprotease, members ofBcl-2 family and others, aberranceof which may lead to
abnormal proliferation, metastasis and invasion of cells, even carcinomas. Furthermore, miR-125 plays a crucial role
inimmunological host defense, especially inresponse to bacterial or viral infections. Inthis review, we summarize
theimplication ofmiR-125family in disease suppression and promotion, focusing oncarcinoma and host immune
responses. We also discussed thepotential ofthis miRNA family as promising biomarkersand therapeutic targets
for different diseases infuture.
Keywords: miR-125 family,Biomarker,Immune response, Therapeutic target, Tumor-suppressor, Tumor-promoter
Introduction expression of miRNAs in almost all types of cancers and
MicroRNAs(miRNAs) are a family of ~22 nucleotide (nt) otherdiseases,theycanpossiblybeusedasbiomarkersfor
small noncoding RNAs that act as crucial posttranscrip- early diagnosis of cancers and other diseases, depending
tional regulators of gene expression through translational ontheir abundance. Inaddition,miRNAsand their target
repression or transcript cleavage [1]. Since miRNAs were genes supply to a general or personalized therapy with
first described as endogenous mediators in C. elegans in pharmaceuticaltargets,showingtheirremarkable valuein
1993 [2], they have been identified to be involved in clinicaltherapy.
the regulation of numerous cellular processes, including Among the most important miRNA families, miR-125
cell differentiation, proliferation, apoptosis and metabolic family has been reported to be implicated in a variety of
homeostasis[3].Inthepastdecade,moreandmorestud- carcinomas and other diseases as either repressors or
ies have demonstrated that aberrant expression of miR- promoters. MiR-125 family is composed of three homo-
NAs is tightly related to the pathogenesis of diseases, logs hsa-miR-125a, hsa-miR-125b-1 and hsa-miR-125-2.
including almost all types of human cancers [4]. A grow- MiR-125a has been found to be located at 19q13, while
ingbodyofstudieselucidatethatmiRNAscanfunctionas miR-125bisverifiedtobetranscribedfromtwolocilocated
either tumor suppressors by down-regulating oncogenic on chromosomes 11q23(hsa-miR-125b-1) and 21q21
targets,ortumorpromotersthroughnegativelyregulating (hsa-miR-125b-2) [6]. Furthermore, miR-125b-1 is impli-
tumor-suppressivetargetmRNAs [5]. Becauseofaberrant cated in some chromosomal translocations like t(11;14)
(q24;q32) and t(2;11)(p21;q23)which leadstoB-cell acute
*Correspondence:[email protected] lymphoid leukemia (B-ALL) or myelodysplasia and acute
1KeyLaboratoryofGeneEngineeringoftheMinistryofEducation,StateKey myeloidleukemia(AML),respectively[7-10].Membersof
LaboratoryforBiocontrol,SchoolofLifeScience,BiotechnologyResearch
Center,SunYat-senUniversity,Guangzhou510275,People’sRepublicof thefamilyplaycrucialrolesinmanydifferentcellularpro-
China cesses like cell differentiation, proliferation and apoptosis
Fulllistofauthorinformationisavailableattheendofthearticle
©2013Sunetal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
Sunetal.JournalofHematology&Oncology2013,6:6 Page2of8
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by targeting many different transcription factors [11], other negative controls in nude mice, suggesting that up-
matrix-metalloprotease[12,13],growthfactors[14]andso regulatedmiR-125bcanpromotetheproliferationandmi-
on. The theme of the present paper, however, is to gration of the disease [18]. In addition, overexpression of
summarize the function of miR-125 family in different miR-125bhasbeeninvestigatedinseveralcancerssuchas
contexts, particularly in disease condition. We mainly pancreatic cancer [33], prostate cancer [34,35], oligo-
focusonfollowingfouraspects:(1)theregulationofmiR- dendroglial cancer [36] and other cancers. Furthermore,
125 at post-transcription level, (2) the function of miR- miR-125bhasbeendemonstratedtoplayakeyroleinthe
125as tumor-suppressiveor tumor-promotingproperties, initiation and development of prostate cancer through
(3)potentialactingofmiR-125asbiomarker,anditspossi- evaluating the effect of miR-125b on xenograft tumor
bilitytobeusedasatherapeutictargetindiseasetherapy, growth in transplanted mice with PC-346C-miR-125b
and(4)theimmune-modulatingfunctionsofmiR-125and cells [35]. Albeit miR-125b has been demonstrated to be
the involvement of this miRNA in immune responses to tumor suppressor in breast cancer by down-regulating
pathogeninfections. ERBB2 and ERBB3 [22], several studies have showed its
property to increase resistance of cancer cells, including
InvolvementofthemiR-125familyinsolidtumors breast cancer cells, to anticancer drug [37], resulting in
A great amount of studies have investigated the relation- subsequent recurrence and metastasis. Surprisingly, in
ships between miRNAs and malignancies, and the results contrast to tumor-suppressive function in breast cancer
show that miRNA deregulation is involved in all types of mentioned above, a very recent study by Tang et al. has
cancer. The different members of miR-125 family have verified that miR-125b also induces metastasis of human
beenreportedcontroversialpropertiesindifferenttypesof breastcancercellsthroughtargetingSTARD13[38].miR-
cancer; they may contribute to the initiation and progres- 125a alsoenhances invasive potential in urothelial carcin-
sion of cancers by acting as either tumor suppressors or omas [39] and is up-regulated in basal cell carcinoma
oncogenes[15-18]. compared with adjacent nonlesional skin [40], while miR-
MiR-125 has been shown its tumor-suppressor func- 125bsuppressesBmf-dependentapoptosisinhumanglio-
tions in several cancers including ovarian cancer [16,19], blastomamultiformecells[41].
bladder cancer [20],breastcancer [21-23],hepatocellular The controversial properties of the miR-125 family in
carcinoma [12,24,25], melanoma [26], cutaneous squa- different solid tumors suggest that miR-125 plays diverse
mous cell carcinoma [13] and osteosarcoma [27]. Wang functions in cancer pathogenesis and progression, while
et al. reported that miR-125a, activated by EGFR, func- the underlying mechanisms on different cell context
tions as a metastatic suppressor in lung cancer cells, need further investigation.
inhibiting tumor formation and tube formation [28]. In
breast cancer, miR-125a and miR-125b were reported PropertiesofthemiR-125familyinhematological
down-regulated in biopsy specimens and as tumor sup- malignancies
pressors [23,29,30] by mediating the ERBB2 and ERBB3 Dysregulation of miRNAs has now clearly been linked to
pathway [22] or by targeting the ETS1 gene [31]. Fur- hematological malignancies, especially to leukemia [42].
thermore, Hajabi et al. found that miR-125b can reduce It has been shown that miR-125b is implicated in some
theexpressionofMUC1oncoprotein,silencingofwhichin subtypes of leukemia induced by chromosomal trans-
breast cancer cells with siRNA promotes DNA damage- location. The chromosomal translocation t(11;14)(q24;
induced apoptosis [32]. Ectopic expression of both q32) found in patients with B-cell acute lymphoblastic
miR-125a [12] and miR-125b [25] can inhibit the prolif- leukemia (ALL)[7,9] leads to an up-regulation of miR-
eration and metastasis of hepatocellular carcinoma. Up- 125b. Moreover, overexpression of miR-125b also occurs
regulated miR-125a significantly inhibits the malignant in patients with myelodysplasia and acute myeloid
phenotypes by repressing the expression of matrix leukemia (AML) carrying the t(2;11)(p21;q23) transloca-
metalloproteinase 11 (MMP11) and vascular endothe- tion [8]. MiR-125b has also been reported to be overex-
lial growth factor A (VEGF-A) both in vitro and in vivo pressedin megakaryoblastic leukemia[43] and APL [44].
[12], while the direct targets of miR-125b in miRNA- Bousquet and colleagues transplanted fetal liver cells
induced inhibition of hepatocellular carcinomacell pro- which ectopic express miR-125b into nude mice to de-
liferation are Mcl-1 and IL6R [25]. cipher oncogenic mechanism of miR-125b [15]. In this
In contrast to the tumor-suppressive properties men- study they found a higher level of miR-125b increased
tioned above, the members of miR-125 family, especially white blood cell count in mice and half of these mice
miR-125b, also act as oncogene in several cancers. Jiang died of diverse leukemia such as B-cell and T-cell ALL,
andcolleaguesobservedthatAN3CAcells,atypeIIendo- or a myeloproliferative neoplasm, suggesting miR-125b
metrial carcinoma cell line, transfected with miR-125b an important role in early hematopoiesis (the function
mimic showed higher tumorogenesis in comparison to then was proved by Chaudhuri [45]). Furthermore, this
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study also demonstrated that miR-125b can shorten the mainly focus on the expression pattern of miR-125, the
latency of BCR-ABL induced leukemia as a secondary targetsandinflammatorypathwayinthisdiseasestillneed
event. Enomoto et al. reported that transduction of miR- tobedeclared
125b-1 in bone marrow cells indeed accelerated myeloid
tumors induced by a C-terminal mutant of CAAT- MiR-125involvedinimmunesystemdevelopmentand
enhancer binding protein (C/EBPα-C(m)) [46], suggest- immunologicalhostdefense
ing that overexpression of miR-125b collaborates with It has been uncovered that miRNAs are tightly asso-
other genetic alterations in the pathogenesis of myeloid ciated with immune system by controlling the destiny of
malignancies. Albeit Enomoto didn’t find leukemia immune cells [56,57], regulating the expression of target
transformationintheirmodel,arecentstudybyBousquet encoding genes, responding to stimulatory cues, and en-
has highlighted the transformation of miR-125b-induced hancing the response of immune cells to potential anti-
leukemia in nude mice [11]. Much to our surprise, miR- gen as well as playing a key role in fate of immune cells.
125b, which has been shown reduced expression in both An example is that, B lymphocyte-induced maturation
aggressive and indolent chronic lymphocytic leukemias protein-1 (BLIMP-1) and IFN regulatory protein-4 (IRF4)
(CLL) patients, its overexpression can change metabolic transcription factors, which are essential for plasma cell
pathwaysincludingglucose,glutathione,lipidandglycero- differentiation, have been demonstrated to be targets for
lipidmetabolisminCLL,suggestingthatmiR-125bplaysa miR-125b. Gururajan and colleagues have evaluated the
vital role for the adaptation ofcell metabolism toa trans- effect of overexpression of miR-125b on B cell differenti-
formed state [47]. However, the mechanism underlying ation in an LPS-responsive B cell line, finding that miR-
differential expression pattern of miR-125b between CLL 125b can repress the differentiation of primary B cell, in
and other types of hematological malignancies is still un- which they found that miR-125b promotes B lymphocyte
known. We speculated that the induced expression of diversificationingerminalcentersbyinhibitingpremature
miR-125binCLLleadstometabolicadaptationassociated utilizationofessentialtranscriptionfactorsforplasmacell
cancer transformation may be caused by very low prolif- differentiation[56].Inaddition,miR-125bisconfirmedto
erativeindexanddefectsinapoptoticpathwaysinthedis- protect B cells from apoptosis through contributing to
ease, while the up-regulated miR-125b leads to acute repression of BCL2 which does a developmental stage-
leukemia may be resulted from hematopoietic stem cell specificregulationduringB-cellmaturation,andderegula-
differentiation block by miR-125b. These speculations tionofmiR-125binresponsetoCD40ligand(CD154)can
needtobefurthervalidated. leadtoproliferationinleukemicBcells[57].
Beyond regulated by cytokine like IL-4 [58] and inter-
ThefunctionallinkofthemiR-125familyinautoimmune feron, miR-125b have also been verified to frequently
diseases regulate expression of signals involved in immune sys-
TheaberrantexpressionofmiR-125wasalsofoundindif- tem. Studies have showed that up-regulated expression
ferent diseases other than cancers, such as autoimmune of miR-125b may enhance type I IFN expression in air-
diseases [48]. For instance, miR-125a has been identified way epithelial cells in eosinophilic chronic rhinosinusitis
down-regulated in systemic lupus erythematosus (SLE), with nasal polyps [53], while negatively regulating TNF-
and negatively regulated expression of the inflammatory α expression in neonatal monocytes[59]. Both signals
chemokine RANTES, which is highly expressed in SLE play crucial roles in immunological host defense, aber-
samples and plays a key role in inflammatory progress rant expression or response of which may result in fatal
[49]. MiR-125a was also reported to be significantly up- diseases. Furthermore, overexpression of miR-125b in
regulated in macrophases following oxidized low density macrophage showed the repression to IFN regulatory
lipoprotein(oxLDL)[50],inducingtheformationofische- factor 4 (IRF4), and elevated responsiveness to IFN-γ,
mic stroke [51]. Moreover, miR-125b acting as pro- potentiating the functional role of macrophages in indu-
inflammation role can be mediated by metal sulfates to cingimmuneresponses [60].
affect the outcome of ischemic stroke [51,52]. Interest- Another important function of miR-125 is in immune
ingly, Zhang and colleagues have found the overexpres- responses to bacterial infection, and even shows to par-
sion of miR-125b in eosinophilic chronic rhinosinusitis take in damage accompanied by pathogenic bacteria.
with nasal polyps, enhancing type I IFN expression Rajaram has illustrated that virulent mycobacterium tu-
through suppressing 4E-BP1 protein expression [53]. In berculosis could take advantage of miR-125b to block
addition, dysregulation of miR-125b has been reported to TNF biosynthesis. Lipomannan from virulent mycobac-
beinvolvedinAlzheimer'sdisease[54]andMyotonicDys- terium tuberculosis induces overexpression of miR-125b,
trophy Type 2 [55]. All together suggest that miR-125 which subsequently binds to the 3' UTR region of TNF
plays important roles in autoimmune diseases. However, mRNA and destabilizes the transcript [61]. Apart from
thus far, most of the studies on autoimmune diseases immune reaction to bacterial infection, a study shows
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that miR-125b plays an important role in anti-viral miR-125b [22]. Experimentally, miR-125-induced down-
defense [62]. MiR-125a interacted with the viral sequence regulation of ERBB2 and ERBB3 has been uncovered to
and markedly suppressed the reporter activity. Subse- reduce cell motility and invasiveness of numerous can-
quently miR-125a was shown to interfere with the viral cers, including breast cancer [22] and endometrial can-
translation, down-regulating the expression of the surface cer[72].
antigen [62]. Interestingly, miR-125b has been verified to Among other targets of miR-125 associated with pro-
contribute to HIV-1 latency [63], acting as an anti-HIV-1 liferation, metastasis and migration, HuR [73], Rock-1
miRNA [64]. MiR-125b, repressing HIV-1 activity, is [74], PDPN [75], STAT3 [27] and STARD13 [38] are five
higherexpressedinrestingCD4+Tcellsincomparisonto important genes identified, which can induce cell metas-
activated CD4+ T cells. The miRNA can bind to the 3' tasis and migration, and in turn enhance tumorigenesis.
endsofHIV-1messengerRNAs,leadingtodestabilization Furthermore, CBFβ, a transcriptional factor involved in
of the transcript, terminally inhibits HIV-1 production hematopoiesis,whichhasbeenconfirmedtobeanewdir-
and prolongs HIV-1 latency in resting CD4+ Tcells [63]. ect target of miR-125b, and ABTB1, an anti-proliferative
In addition, a recent study has found that morphine was factor targeted by miR-125b, also contribute to block
shown to down-regulate the expression of anti-HIV miR- differentiation and proliferation in leukemia, respect-
NAs including miR-125b in cultured human monocytes ively [11,76].
[64], which suggests that morphine may have potential to Othertargetshavebeendemonstratedincludingmatrix-
activate latent HIV-1 in resting CD4+ Tcells and macro- metalloprotease MMP11[12], MMP13 [13], Kurppel-like
phagesbyinhibitingrelatedmiRNAsexpression. factorKLF13[49],c-Jun[26],ARID3B(AT-richinteractive
In conclusion, miR-125 family plays crucial roles in domain 3B) [16,77], ARID3A (AT-rich interactive domain
immune system development and immunological host 3A) [78], germ layer specification [79] and hematopoiesis
defense, including regulating differentiation of immune regulator LIN28A [45], growth factors such as VEGF-A
cells, responding to stimulatory cues in many different [12] and IGF-II [14], and growth factor receptors like
signal pathways involved in immune system, controlling FGFR2[80],etal.
expression of target genes, products of which partake in It is necessary to mention that the same target may
immune reactions as well as in immune responses to have different functions in different cellular processes,
bacterialinfectionandtoviralinfection. cellular context, and diseases. For example, ARID3B ele-
vates the epithelial-to-mesenchymal transition (EMT) in
TheregulatorynetworkofmiR-125familyindisease human ovarian cancer [16], while increases cell migra-
pathogenesis tion in breast cancer [77]. Consequently, target genes of
Asprevious reported, miR-125family playsanimportant specific cell-type may be useful in a more targeted and
role in normal cell homeostasis, cell metastasis and dif- precise therapybymiRNAs.
ferent diseases. Current progression also revealed a As summarized in Figure 1, the targets of miR-125
number of the miR-125 family target genes and their family are involved in different types of diseases patho-
regulation pathways, which could supply the feasibility genesis. MiR-125 can act as cancer promoter or cancer
of using miR-125 as a therapeutic strategy to suppress repressor depends on the cell context, among which, the
diseases. mitochondrial apoptosis pathway is the well illustrated
Members of Bcl-2 family and ones else involved in roleofmiR-125withthetwofaces(asshowninFigure2).
apoptosis are an important group of miR-125 targets. The down regulated miR-125 caused breast cancer but
Anti-apoptotic members of Bcl-2 family such as Bcl-w the up regulated miR-125 induced chemoresistance,
[65], Bcl-2 [66], Mcl-1 [65,67], and Bak-1 [11,44,68,69] and higher expression of miR-125 promoted ALL or
acting as the Bcl-2 homologous antagonist, and others AML nevertheless reduced expression of miR-125b
involved in apoptosis like P53 [69], TP53INP1 [11,18], resultedinmetabolicpathwaystransformedinCLL.Re-
TNFAIP3 [70], p38α [71] et al., have all been demon- search on miR-125 in leukemia and breast cancer
stratedtobedirecttargetsofmiR-125inpreviousstudies. model may provide a new insight into current miRNA
Aberrant expression of miR-125 leads to up-regulation of research.
Bcl-2, Mcl-1 et al. and down-regulation of Bak-1,
TP53INP1 et al. and consequently to protect cells from PotentialofmiR-125fordiseasediagnosisandtherapy
apoptosis,whichinturnpromotestumorigenesis.Besides, Some protein coding genes have been reported playing
p38α expression repressed by miR-125b is required for critical roles in tumor initiation and progression, and
protectingcellsfromUV-inducedapoptosis. their expression levels are correlated with clinical out-
ERBB2, which enhances kinase-mediated activation of come [81,82]. Growing studies demonstrate the advan-
downstream signaling pathways such as MAPK, has tages using miRNA as biomarkers for cancer and
been verified to be the target for both miR-125a and disease. The reviews above have shown that expression
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Figure1SchematicdiagramofthetargetsofmiR-125involvedindifferenttypesofdiseasepathogenesis.
level of miR-125 family is distinguished in various types are inversely correlated with aggressiveness and poor
of disease, implying that the miR-125 could predict dis- prognosis in HCC, and could serve as the bio-marker
ease onset and might potentially serve as prognostic for HCC diagnosis and prognosis. Expression profiling
marker in disease-derived tissues and possibly in serum. of miR-125b is a potential marker for thyroid cancer as
For example, decreased miR-125a has been observed in it is overexpressed in thyroid cancer and its level has
hepatocellular carcinoma (HCC) tissues compared with remarkably distinction between benign and malignant
matched adjacent liver tissues, and associated with thyroid neoplasms [83]. In human colorectal cancer,
patients' aggressive pathologic features [12]. Moreover, Nishida and colleagues have evaluated expression of
Hong and colleagues haveuncovered that the expression miR-125b in 89 colorectal cancer cases, and interestingly
levels of miR-125b were much lower in HCC tissues found that the high miR-125b expression group not only
than in non-tumor liver tissues [25], indicating that both showed a greater incidence of advanced tumor size and
miR-125a and miR-125b have low expression level and tumor invasion, but also had a significantly poorer prog-
nosis compared to the low expression group [84], sug-
gesting that miR-125b could be an important prognostic
marker for colorectal cancer patients. The miRNA de-
regulation may be also associated with clinical relevance
linking to key gene mutations [85]. For example, down-
regulation of miR-125b was found significant correlation
with TP53 mutation status [86]. Taken together, miR-
125 family has great perspective as a diagnostic and
prognostic biomarker. Moreimportantly, agreat amount
ofstudieshavedemonstratedthatcirculating miRNAsin
human serum and other body fluids can be used as bio-
markers for cancer and other diseases [87,88]. This po-
tential of miRNAs provides a possibility to carry out
non-invasive analyses to clinicians, which can be per-
Figure2ThetargetsofmiR-125inmitochondrialapoptosis formed easily in a large number of clinical samples.
pathway.MiR-125playsimportantrolesinmitochondrialapoptosis However, standard reference controls are needed in
pathwaybytargetingpro-apoptosisoranti-apoptosisgenedepends
order to ensure reliable and correct measurements of
onthecellcontext.
miRNA levels.
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Moreover, ongoing studies have also suggested the po- Authordetails
tential of the miRNA associated with therapy [89,90]. As 1KeyLaboratoryofGeneEngineeringoftheMinistryofEducation,StateKey
LaboratoryforBiocontrol,SchoolofLifeScience,BiotechnologyResearch
mentioned above, miR-125 family may contribute to the Center,SunYat-senUniversity,Guangzhou510275,People’sRepublicof
initiation and progression of diseases by acting as either China.2NorthwestA&FUniversity,Yangling,Shanxi712100,China.
suppressors or promoters in a number of cancers and
Received:21December2012Accepted:10January2013
other diseases [16,17,22,23,25,28,29], re-introduction of
Published:15January2013
synthetic miR-125 or its antisense at specific sites could
becomeapossibletreatmentoption.
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