Journal of Cancer Therapy, 2013, 4, 466-474
http://dx.doi.org/10.4236/jct.2013.43A057 Published Online March 2013 (http://www.scirp.org/journal/jct)
MicroRNAs as Targets and Tools in B-Cell Lymphoma
Therapy
Kalman Szenthe1, Katalin Nagy2, Krisztina Buzas3,4, Hans Helmut Niller5, Janos Minarovits3*
1RT-Europe Nonprofit Research Center, Mosonmagyarovar, Hungary; 2Department of Oral Surgery, Faculty of Dentistry, University
of Szeged, Szeged, Hungary; 3Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of
Szeged, Szeged, Hungary; 4Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Szeged,
Hungary; 5Department of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
Received January 23rd, 2013; revised February 25th, 2013; accepted March 5th, 2013
ABSTRACT
MicroRNAs (miRNAs) are posttranscriptional regulators fine-tuning the level of most messenger RNAs (mRNAs) and
proteins in mammalian cells. Their expression is dysregulated in neoplastic cells and upregulated or downregulated
miRNAs play an important role in tumorigenesis. Changes in the miRNA transcriptome appear to be suitable markers
for the differential diagnosis of various B-cell lymphoma types and there are therapeutic attempts to normalize the ex-
pression level of key cellular miRNAs involved in lymphomagenesis. In this review we wish to outline the most recent
developments in the application of sophisticated, chemically modified antisense oligonucleotides and their nanoparticle
complexes to suppress oncogenic miRNAs. These advances form the basis of a new therapeutic approach that may
complement current protocols for B-cell lymphoma therapy. Anti-cytokine therapy aiming at the removal of cytokines
that activate key oncomirs, and switching on silenced tumor suppressor miRNAs by epigenetic drugs might also be
considered, on the long run, in the treatment of well defined B-cell lymphoma types.
Keywords: MicroRNAs; B-Cell Lymphoma Therapy; Antisense Oligonucleotides; Anti-Cytokine Therapy; Epigenetic
Drugs
1. Introduction
Recently, microRNAs (miRNAs) emerged as a new class
of regulators of a wide variety of physiological processes
[1]. miRNAs usually downregulate messenger RNA
(mRNA) levels and protein levels by binding to comple-
mentary regions on their target mRNAs. miRNA-mRNA
association may either facilitate mRNA breakdown or
block mRNA translation.
Dysregulated expression of certain miRNAs plays a
role in the development of malignant neoplasms [2-4].
Increased level of several miRNAs, called oncomirs, fa-
cilitates oncogenesis and tumor progression. Other mi-
RNAs act similarly to the products of tumor suppressor
genes: their reduced expression may result in uncontrol-
led cell proliferation and altered cellular behaviour.
2. miRNAs as Pleiotropic Posttranscriptional
Regulators in Normal and Neoplastic Cells
2.1. Biogenesis of MicroRNAs
miRNAs are transcribed in most cases by RNA poly-
merase II (Pol II) from independent transcription units or
they are processed from introns of transcripts (for review
see [1,3]). Typically the primary Pol II product (pri-
miRNA) is processed in the nucleus by the RNase III
Drosha resulting in a stem and loop structure called pre-
miRNA. The approximatively 70 nucleotide long pre-
miRNA molecule is carried to the cytoplasm by Exportin
5, a nuclear export protein. As a next processing step,
DICER1, a cytoplasmic RNAse III enzyme removes the
loop of the pre-miRNA and the resulting double stranded
RNA is loaded onto an Argonaute (Ago) protein, a com-
ponent of the RNA-induced silencing complex (RISC).
One strand of the approximately 22 nucleotide long du-
plex RNA represents the guide strand or mature miRNA
that remains associated with Ago, whereas the other
strand is degraded. As few as 6 nucleotides of the mature
single stranded miRNA (nucleotides 2 - 7) form the
“seed region” that plays a major role in selecting the 3’
untranslated region (3’ UTR) of the target mRNA. Be-
cause the seed region, where full complementarity is re-
quired with the target mRNA for RISC function, is short,
a miRNA may potentially recognize multiple mRNA tar-
gets. It is also worthy to note, however, that the very
*Corresponding author.

MicroRNAs as Targets and Tools in B-Cell Lymphoma Therapy 467
same 3’ UTR may bind more than one miRNA species
(reviewed in [1,3]).
2.2. Dysregulation of miRNA Expression in
B-Cell Lymphomas
The pattern of miRNA expression in neoplastic cells dif-
fers from the miRNA transcriptome (miRNAome) of
their normal counterparts (for review see [3]). In addition,
the expression signatures of miRNAs appear to be suit-
able markers for the differential diagnosis of various ma-
lignant tumors including the different B-cell lymphoma
types [5]. Some of the differentially expressed miRNAs
apparently play an important role in the initiation and
maintenance of the malignant behaviour, which implies
that overexpression or inhibition of key microRNAs may
revert the malignant phenotype. The best characterized
miRNAs most frequently upregulated or downregulated
in the major B-cell lymphoma types are summarized in
Tables 1 and 2 (for a comprehensive review see also [4]).
Tables 1 and 2 also show their target mRNAs and puta-
tive role in lymphomagenesis. It is important to note
that—depending on the cellular context—the very same
miRNA may either facilitate or inhibit tumorigenesis.
Thus, miR-155, a multifunctional regulator molecule up-
regulated in diffuse large B-cell lymphomas (DLBLs)
and Hodgkin lymphomas acted as an oncomir in a trans-
genic mouse model, where its ectopic expression resulted
in pre-B cell proliferation and lymphoblastic leukemia/
lymphoma [6-8]. All these changes were attributed to a
release of the interleukin-6 (IL-6) pathway from its in-
hibitory control by miR-155 [9]. In gastric cancer cells,
however, miR-155 was downregulated and its overex-
pression suppressed cell migration and invasion. Thus, in
gastric cancer cells miR-155 acted as a tumor suppressor
targeting SMAD2, a component of the transforming
growth factor beta (TGFβ) signalling pathway [10]. In
addition, Babar et al. observed that although induction of
high levels of miR-155 in a tetracycline-controlled knock-
in mouse model caused the development of disseminated
pre-B cell lymphoma, highly elevated miR-155 expres-
sion in the brains of the same mice was insufficient to
induce brain tumors [11].
2.3. Attempts to Normalize the Expression of
Key Cellular miRNAs in Various B-Cell
Lymphoma Types
As illustrated above, miR-155 has emerged as a pleio-
tropic regulator of numerous biological processes. Thus,
it became a logical therapeutic goal to attenuate its on-
cogenic functions to complement, on the long run, cur-
rent protocols for lymphoma treatment. High affinity
binding of anti-miR oligonucleotides to distinct micro-
RNAs may sequester their target without causing its de-
gradation, whereas a lower-affinity binding promotes
miRNA degradation [12]. Early in vivo attempts of se-
quence specific silencing by short hairpin RNAs failed
due to the activation of the immune system, toxic off-
target effects, and saturation of the endogenous micro-
RNA pathway (reviewed in [13,14]). However, more so-
phisticated, chemically modified antisense oligonucleo-
tides including locked nucleic acid (LNA) oligonucleo-
tides, peptide nucleic acids (PNAs) conjugated either to a
cell-penetrating peptide or polylysine, and cholesterol-
conjugated RNAs called “antagomirs” proved to be ef-
fective inhibitors of microRNAs both in vitro and in vivo
[14-18]. Fabani et al. reported that a peptide nucleic acid
(PNA) oligonucleotide containing four D-lysine residues
to ensure proteolytic stability and enhanced cellular
uptake could inhibit miR-155 both in vitro and in the
spleens of experimental mice receiving 50 mg PNA/kg/
day for 2 days [16].
To explore the advantages of the nanoparticle delivery
systems that permit targeting of miRNA inhibitors to se-
lected cells and tissues, anti-miR-nanoparticle complexes
were constructed and tried successfully in clinically ac-
ceptable and therapeutically affordable doses in mice [11,
19,20]. Babar et al. demonstrated that in spite of the po-
tential difficulties of cellular internalization, antisense pe-
ptide nucleic acids encapsidated into biodegradable poly
(lactic-co-glycolic acid) (PLGA) particles coated with
penetratin inhibited miR-155 and decreased the growth
rate of pre-B-cell tumors in a knock-in mouse model [11].
Although penetratin facilitates uptake into various cell
types, it was observed that the systematically adminis-
tered nanoparticles showed preferential targeting to tu-
mor tissue.
miR-155 is indispensable for the development of an
optimal T cell dependent antibody response and controls
T helper cell differentiation by regulating cytokine pro-
duction [21]. miR-155 expression leads to elevated tumor
necrosis factor alpha (TNFα) levels whereas TNFα in-
duces miR-155 expression. In a subgroup of diffuse large
B cell lymphoma, called activated B cell-like or non-
germinal centre (ABC or non-GC) DLBC, augmented
miR-155 expression was found due to an increased TNFα
production. The high miR-155 level could be reduced in
non-GC DLBC cell lines cultured in vitro by adding
eternacept, a soluble TNFα receptor or infliximab, a neu-
tralized humanized monoclonal antibody against TNFα,
to the culture medium [22]. These observations indicate
that anti-cytokine therapy could potentially be used to
normalize the expression of miR-155, a cytokine-regu-
lated microRNA, in a subset of patients with DLBC.
Such a treatment may improve the prognosis and re-
lapse-free survival of the ABC/non-GC group of DLBC.
Reactivating silenced genes coding for miRNAs that in-
hibit cell proliferation similarly to tumor suppressor pro-
teins appears to be a promising strategy in lymphoma

MicroRNAs as Targets and Tools in B-Cell Lymphoma Therapy 468
Table 1. MicroRNAs upregulated in B-cell lymphomas.
Lymphoma type miRNA (references) Comment
miR-19b [35] component of the miR-17-92 cluster that promotes cell proliferation and
angiogenesis, represses apoptosis
miR-17-5p [36] component of the miR-17-92 cluster
miR-143 [37]
miR-145 [37]
miR-145 or miR-143 play a tumor-suppressive role in various cancers; Ras
activation represses the miR-143/145 cluster
miR-155 [5,38] oncomir, regulates proliferation, promotes to cell survival
miR-29b [5,39] regulates P53
miR-146a [5] down-regulates TRAF6, IRAK1, the Toll-like and cytokine receptor pathway
adaptor molecules
miR-365 [5] direct negative regulator of IL-6
miR-30b [5,40] blocks terminal B-cell differentiation
let-7f [5] let-7 family member, tumor suppressor
miR-9 [5] activated by MYC/MYCN; regulates E-cadherin
Diffuse large B-cell
lymphoma (DLBCL)
miR-34b [5] tumor suppressor, its promoter is methylated in melanoma
miR-197 [5,41] represses the tumor suppressor gene FUS1
miR-206 [5] inhibits the TGF-β-mediated up-regulation of HDAC4
miR-370 [5] targets TRAF4
miR-19a [35]
miR-20a [35]
miR-92 [35]
component of the miR-17-92 cluster
miR-483 [5] cooperates with IGF2; upregulated in various carcinomas
Chronic lymphocytic
leukemia/small lymphocytic
lymphoma (CLL/SLL)
miR-485 [5] putative down-regulator of Nuclear factor (NF)-YB
miR-150 [5,42] targets c-Myb; plays a key role in B-cell differentiation
miR-221 [43] required for angiogenesis; promotes endothelial cell migration and proliferation
m
Nodal marginal zone B-cell
lymphomas iR-223 [43] suppresses cell proliferation by targeting IGF
let-7 family [5]
let-7f [43]
tumor suppressor
Splenic marginal zone
B-cell lymphoma miR-144/451 family [5] regulates erythroid development and susceptibility to oxidative stress
miR-200 cluster [5,44] inhibits metastasis formation, blocks epithelial–mesenchymal transition (EMT);
maintains the epithelial phenotype through targeting the repressors of E-cadherin
miR-429 [5] targets MYC
Marginal zone B-cell
lymphoma/MALT
miR-141 [5] targets p38α, modulates the oxidative stress response
miR-138 [5] regulates P53
miR-9, miR-9* [5,36] NF-κB regulators induced by MYC; target E-cadherin
miR-155 [36] oncomir, regulates cell proliferation, enhances cell survival
miR-210 [36 targets the apoptosis-inducing factor AIFM3
miR-301 [36] mediates proliferation via NF-κB
miR-143 [37]
miR-145 [37]
tumor-suppressor Ras activation represses the miR-143/145 cluster
miR-221 [37] required for angiogenesis; promotes endothelial cell migration and proliferation.
let-7b, let7i [37] let-7 family members, tumor suppressors
Follicular lymphoma (FCL)
miR-494 [43] regulates PTEN expression

MicroRNAs as Targets and Tools in B-Cell Lymphoma Therapy 469
Continued
miR-183 [5] targets EGR1, a tumor suppressor
miR-200c [5,44]
inhibits metastasis formation and epithelial–mesenchymal transition (EMT), by
maintaining the epithelial phenotype through directly targeting the transcriptional
repressors of E-cadherin, ZEB1 and ZEB2
miR-182 [45] facilitates metastasis formation
miR-181 [45] mediates proliferation, overexpression can be apoptotic
miR-155 [25] oncomir; regulates proliferation, enhances cell survival
Mantle cell lymphoma
miR-210 [25] targets apoptosis-inducing factor, mitochondrion-associated, 3, (AIFM3)
miR-17-3p [5]
miR-17-5p [46]
miR-18a [5]
miR-19a [5,35]
miR-19b [5,35]
miR-20a [46]
Burkitt’s lymphoma (BL)
miR-92 [5]
component of the miR-17-92 cluster
miR-17-5p [40]
miR-20a [40] component of the miR-17-92 cluster
miR-9 [40] activated by MYC/MYCN; regulates E-cadherin
miR-30b/c [40] blocks terminal B-cell differentiation
Primary central nervous
system lymphoma (PCNSL)
miR-155 [40] oncomir, regulates cell proliferation, enhances cell survival
miR-29a, b [39,47] regulates P53
let-7a, f, g [47] let-7 family member, tumor suppressor
miR-21 [47] modulates tumorigenesis through regulation of BCL-2
miR-125b [47] inhibits cell proliferation
miR-181a [47] miR-181a overexpression can be apoptotic
miR-155 [48,49] oncomir, regulates proliferation, enhances cell survival
miR-206 [48] increases histone acetylation, and transcription
Lymphoplasmocytic
lymphoma (Waldenström’s
macroglobulinemia, WM)
miR-223 [47] suppresses cell proliferation by targeting IGF
treatment [23]. Gastric marginal zone B-cell lymphoma
of MALT type (MALT lymphoma), an indolent disease,
may progress to a more aggressive disease, gastric di-
ffuse large B-cell lymphoma (gDLBCL) due to overex-
pression of the Myc oncoprotein [24]. Myc transcription-
ally represses a series of miRNAs including miR-34a,
that has antiproliferative properties when overexpressed
in DLBCL cells. This effect could be attributed to the
suppression of FoxP1, a pioneer transcription factor and
miR-34a target. Craig et al. speculated that miR-34a re-
placement therapy could be beneficial in miR-34a nega-
tive hematopoietic malignancies, including gDLBCL
[24]. Transcriptional silencing of miR-29 in mantle cell
lymphoma is also associated with Myc [25]). In a study
performed by Zhao et al., miR-29 levels were associated
with prognosis: patients with significantly reduced ex-
pression of miR-29 had a short survival compared with
those who expressed relatively high levels [26]. It was
observed that Myc repressed miR-29 through EZH2, a
component of the Polycomb repressor complex that en-
sures the inheritance of gene expression patterns from
cell generation to cell generation, and the histone de-
acetylase HDAC3, that also marks repressed chromatin
domains [25]. Epigenetic drugs inhibiting both EZH2
and HDAC3 could restore miR-29 expression and sup-
pressed lymphoma growth both in vitro and in vivo.
These studies suggest that epigenetic therapy might be
efficient in the treatment of certain B-cell malignancies.
In addition to gDLBCL and mantle cell lymphoma, Bur-
kitt’s lymphomas carrying characteristic c-Myc trans-
locations may also fall into this category.
2.4. Cellular and Viral miRNAs as Possible
Therapeutic Targets in Virus-Associated
Lymphomas
The pattern of Epstein-Barr virus (EBV), a human gam-
maherpesvirus, is associated with a series of malignant
tumors, including B-cell lymphomas (reviewed in [27].

MicroRNAs as Targets and Tools in B-Cell Lymphoma Therapy 470
Table 2. MicroRNAs down-regulated in B-cell lymphomas.
Lymphoma type miRNA (references) Comments
miR-145 [36] tumor suppressor in various cancers; Ras activation represses the miR-143/145
cluster
miR-150 [36,42] regulates c-Myb; and plays a key role in B-cell differentiation
miR-139 [36] suppresses metastasis and progression of liver carcinoma.
miR-149 [36] miR-149* induces apoptosis by inhibiting Akt1 and E2F1
miR-320 [36] reduces ERK1/2 protein levels
Diffuse large B-cell
lymphoma (DLBCL)
let-7e [36] tumor suppressor
let-7 family (a, d, e, f, g) [5] let-7 family member, tumor suppressor effect
miR-100 [5] suppresses IGF2 in breast cancer
miR-125a [5] targets the negative NF-κB regulator TNFAIP3
miR-126, miR-126* [5,50] diagnostic for acute myeloid leukemia cases with common translocations
miR-143 [5] tumor-suppressor; repressed by Ras activation.
miR-146a [5] targets TRAF6 and IRAK1, the Toll-like and cytokine receptor pathway adaptor
molecules
miR-15b [51]
miR-16 [51]
miR-15 and miR-16 are direct transcriptional targets of E2F1
miR-17-5p [5] component of the miR-17-92cluster
miR-20a,b [5]
miR-182 [5] facilitates metastasis formation
miR-223 [5] suppresses cell proliferation by targeting IGF
miR-34a [5] tumor supressor
miR-365 [5] direct negative regulator of IL-6
miR-451 [5] regulates erythroid development and susceptibility to oxidative stress
miR-7 [5] inhibits tumor growth and metastasis
miR-9, miR-9* [5] activated by MYC/MYCN, regulates E-cadherin
Chronic lymphocytic
leukemia/small lymphocytic
lymphoma (CLL/SLL)
miR-98 [5,41] targets the tumor suppressor FUS1
Nodal marginal zone B-cell
lymphoma miR-370 [52] down-regulated in gastrointestinal tumors with 14q loss
miR-141 [5,44]
the miR-200 family inhibits the initiating step of metastasis, the epithelial
mesenchymal transition (EMT), by maintaining the epithelial phenotype through
directly targeting the transcriptional repressors of E-cadherin, ZEB1 and ZEB2
Splenic marginal zone
B-cell lymphoma
apoptosis-inducing factor, mitochondrion-associated, 3 (AIFM3) could be a direct
target gene of miR-210
Marginal zone B-cell
lymphoma/MALT miR-126* [5,50] diagnostic for acute myeloid leukemia cases with common translocations.
miR-320 [36] reduces ERK1/2 protein levels and glucose induced ERK1/2 phosphorylation
miR-149 [36] induces apoptosis by inhibiting Akt1 and E2F1
Follicular lymphoma (FCL)
miR-139[36] suppresses metastasis and progression of hepatocellular carcinoma by
down-regulating Rho-kinase 2.
miR-126* [45,50] it’s expression distinguishes acute myeloid leukemia cases with common
translocations
miR-29a, b, c [25,39] regulates P53
miR-150 [25,42] regulates c-Myb expression; plays a key role in B-cell differentiation
Mantle cell lymphoma
miR-15a, b [25] miR-15 is a direct transcriptional targets of E2F1 cosing proliferation

MicroRNAs as Targets and Tools in B-Cell Lymphoma Therapy 471
Continued
let-7 family (a, d, e, f, g) [5] tumor suppressor
miR-29 family a, b, c [5,39] regulates P53
miR-451 [5] regulates erythroid development, homeostasis and susceptibility to oxidative stress
miR-146a [53] down-regulates TRAF6 and IRAK1, the Toll-like and cytokine receptor pathway
adaptor molecules
miR-150 [5,42] regulates c-Myb; plays a key role in B-cell differentiation
Burkitt’s lymphoma (BL)
miR-155 [53] oncogenic; regulates cell proliferation, enhances cell survival
miR-145 [40] tumor-suppressor
Primary central nervous
system lymphoma (PCNSL) miR-214 [40] targets ATF4
miR-9 [47-49] activated by MYC/MYCN; regulates E-cadherin
miR-152 [47] tumor suppressor
miR-182 [47] facilitates metastasis formation
miR-15a [48] tumor suppressor
Lymphoplasmocytic
lymphoma (Waldenström’s
macroglobulinemia, WM)
miR-16 [48] tumor suppressor
One of the viral oncogenes expressed in nasopharyngeal
carcinomas, post-transplant lymphomas, EBV-associated
Hodgkin disease and in vitro transformed lymphoblastoid
cell lines (LCLs) encodes a transmembrane protein called
latent membrane protein 1 (LMP1) that affects the levels
of certain cellular microRNAs by activating the NF-κB
pathway. Cameron et al. observed that LMP1 induced
miR-146a expression, down-regulating the products of a
group of interferon-responsive genes [28]. miR-155, im-
plicated in the development of B cell lymphomas, was
also upregulated by LMP1 [29]. These virus-induced cel-
lular miRNAs as well as the EBV-encoded miRNAs (re-
viewed in [30]) are also potential targets of lymphoma
therapy.
2.5. miRNAs as Potential Target Molecules in
Radiotherapy and Chemotherapy of Mantle
Cell Lymphoma
Mantle cell lymphoma (MCL), comprising 5% - 10% of
human B-cell malignancies is considered to be incurable
with standard immuno-chemotherapy [31]. For this rea-
son, a novel therapeutic strategy was elaborated, based
on the delivery of radioisotopes to the tumor tissue using
monoclonal antibodies. Anticipating the development of
radioresistant MCL cells, Jiang et al. studied the effect of
miRNA-17-92, an oncomir upregulated in various neo-
plasms, on radiosensitivity of a human MCL cell line in
vitro [32]. They observed that over-expression of mi-
RNA-17-92 increased the survival of irradiated cells by
indirectly up-regulating expression of the AKT protein
kinase [32]. Thus, suppressing miRNA-17-92 may im-
prove, in principle, the efficiency of MCL radiotherapy.
It is worthy to note that another miRNA, miR-155, could
be induced by hypoxia and protected lung cancer cells
from radiation [33]. Treatment with anti-miR-155 mole-
cules, however, radiosensitized the cells in vitro. Over-
expression of miRNA-17-92 cluster inhibited chemothe-
rapy-induced apoptosis in MCL cell lines in vitro [34].
miR-17-92 targeted a protein phosphatase involved in the
negative regulation of the PI3K/AKT pathway, resulting
in AKT activation. Rao et al. suggested that targeting the
miRNA-17-92 cluster could be a plausible approach in
MCL chemotherapy [34].
3. Conclusion
Recent developments in the synthesis of sophisticated,
chemically modified antisense oligonucleotides targeting
oncomirs and the use of anti-miR nanoparticle complexes
made possible the development of new therapeutic ap-
proaches that may complement current protocols for B-
cell lymphoma therapy. Anti-cytokine therapy aiming at
the removal of cytokines that activate the biogenesis of
key oncomirs might also be considered in case of well
defined patient groups. Suppression of oncomir expres-
sion may successfully complement, on the long run, radio-
therapy and chemotherapy of certain B-cell lymphoma
types. In addition, switching on silenced tumor suppres-
sor miRNAs by epigenetic drugs also appears to be a
promising strategy in B-cell lymphoma treatment.
4. Acknowledgements
We are grateful to Ms. Zsófia Papp for her help in the
preparation of the manuscript.
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