Received: 29 January 2019 | Revised: 18 March 2019 | Accepted: 19 March 2019

DOI: 10.1002/jcp.28607

REVIEW ARTICLE

The potential role of miR‐29 in health and cancer diagnosis,

prognosis, and therapy

Mohsen Alizadeh1 | Ali Safarzadeh1 | Fatemeh Beyranvand2 | Fatemeh Ahmadpour3 |

Khalil Hajiasgharzadeh 1
| Amir Baghbanzadeh 1
| Behzad Baradaran 1

1
Immunology Research Center, Tabriz
University of Medical Sciences, Tabriz, Iran Abstract
2
Department of Pharmacology and miR‐29 family is one of the small noncoding RNAs and has a very important role in
Toxicology, Faculty of Pharmacy, Lorestan
many physiologic and pathologic functions through regulating the target genes that
University of Medical Sciences,
Khorramabad, Iran play roles in various bioprocesses such as proliferation, survival, apoptosis, and
3
Department of Biochemistry, Faculty of angiogenesis. Thus, we aim to survey the potential of the miR‐29 family in normal
Medicine, Ahvaz Jundishapur University of
Medical Sciences, Ahvaz, Iran model and development and progression of malignancy in this study. In addition, the
potential role of miR‐29 family has been studied as the clinical marker for the
Correspondence
Behzad Baradaran, Immunology Research diagnosis and prognosis of many cancers as the potential targets to treat cancer.
Center, Tabriz University of Medical Sciences, Moreover, it was stated in summary that the herbal compounds can regulate miR‐29
Daneshghah Ave, Tabriz 5166614766, Iran.
Email: baradaranb@tbzmed.ac.ir family in cancers. Therefore, regulating the expression of the miR‐29 family in a
variety of cancers can be a new strategy to obtain better results from cancerous
patients’ treatment in the future.

KEYWORDS
cancer treatment, herbal compounds, malignancy, miR‐29 family

1 | INTRODUCTION but have similar performance for similarities in their mature

microRNAs (miRNAs) are a group of noncoding RNAs with <25
nucleotide length and influences the gene expression after transcription
(Wahid et al., 2010). Hundreds of genes code these RNAs in human
genomes. It is estimated that miRNAs control about 30% of protein‐
coding genomes (Shenouda & Alahari, 2009). miRNAs can regulate
biological activities through suppressing transcription and messenger
RNAs (mRNAs) cleavage in humans, animals, and plants. Recent studies
have shown very important roles in many biological performances for
this class of RNAs such as their role in differentiation, development,
metabolism, and related processes to cancer, and even diseases such as
diabetes, Alzheimer, and so forth (Lee et al., 1993).
miR‐29 family is one of such small noncoding RNAs. This family is
composed of three elements of hsa‐miR‐29b, hsa‐miR‐29a, and hsa‐
miR‐29c. miR‐29b‐1 and miR‐29b‐2 are called by the same title of
miR‐29b with equal mature sequences. miR‐29b2 and miR‐29c genes
are located on chromosome 1 (1q32.2) and miR‐29a and miR‐29b1
genes are located on chromosome 7 (7q32.3; Kriegel et al., 2012).
miR‐29 family members are coded from two different chromosomes
19280 | © 2019 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/jcp
sequence. This family has a very important role in regulating the
target genes in many bioprocesses such as proliferation, survival,
apoptosis, and angiogenesis. Although the miR‐29 family is involved
in the extensive range of biological processes, most studies have
focused on the pathological activity and tumor suppression activity in
various cancers. In this review, we will study the potential role of the
miR‐29 family in health and cancer.
2 | THE R OLE O F miR ‐2 9 F A M I LY I N
HEAL TH
Recent studies have shown that miR‐29 family can have regulating
activity in various body parts such as immune system (Steiner et al.,
2011), epithelial cell polarity (Gebeshuber et al., 2009), reproduction
(Takeda & Tanabe, 2016), growth (Kamran et al., 2015), hematopoiesis
(Hu et al., 2015), muscle function (Chikenji et al., 2016), and skeleton
(Kapinas et al., 2010; Figure 1). In the following parts, through a large
number of studies, we have detailed some of the most important
J Cell Physiol. 2019;234:19280–19297.

ALIZADEH ET AL.
F I G U R E 1 Regulating activity of the miR‐29 family in the maintenance of healthy tissues function in various body parts. INF‐γ: interferon γ;
IL‐23: interleukin 23; TGF‐β: transforming growth factor β; Th1: type 1 T helper [Color figure can be viewed at wileyonlinelibrary.com]
studies that tried to identify some important targets for miR‐29 in
healthy condition (Table 1).
2.1 | Immune system
miR‐29 family has an important role in the healthy and sick individual
immune system regulation. Studies have shown miR‐29b controls the
innate and adaptive immune response through targeting IFN‐γ‐
producer mRNA (Steiner et al., 2011). T helper cells without miR‐29b
express interferon γ (IFN‐γ) nonnaturally because miR‐29 suppresses
IFN‐γ production by two genes of T‐bet and Eomes. In a way that T‐
bet and Eomes gene expression have a reverse relationship with miR‐
29 (Steiner et al., 2011). miR‐29a/b plays a role in regulating Th1
differentiation because of miR‐29a/b expression is increased in CD4+
T memory cells and in the activating process of other T cells in
multiple sclerosis patients (Smith et al., 2012). Furthermore, reduced
miR‐29a expression defects the proliferation of B cells and antibody
production, and a reduction of T lymphocyte activation (van
Nieuwenhuijze et al., 2017).
The upregulation of interleukin 21 (IL‐21) in the infected patients
in human immunodeficiency virus (HIV) shows a positive correlation
with increasing miR‐29 family expression, which can indicate the
natural resistance of the immune system against HIV virus (Ortega
et al., 2018). Moreover, miR‐29 family expression is increased in
responding to the receptor signals of NOD2. This increase negatively
regulates IL‐23 through targeting p40 and IL‐23 directly and
probably by reducing activating transcription factor 2 (Brain et al.,
2013). In addition, miR‐29 suppresses soluble ST2 (sST2) expression
(which has a role in allergenic inflammation and is an IL‐13 receptor)
in bronchial epithelial cells (Igarashi et al., 2018).
2.2 | Apoptosis
miR‐29 family members cause apoptosis by increasing P53 levels as it
is elucidated that miR‐29 family directly suppresses P85a and
CDC42 genes, which are the negative regulator of P53 (Park et al.,
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| 19281
2009). miR‐29b expression induction in KMCH cells reduced the
Mcl‐1 protein expression, which is an antiapoptotic factor. As a
result, the cancerous cells had apoptosis in the confrontation with
tumor necrosis factor‐related apoptosis inducing ligand (Mott et al.,
2007). miR‐29c targets and controls c‐Jun expression in endometrial
cells by preventing cells proliferation and invasion and finally induces
apoptosis (Long et al., 2015). Hyperglycemia finally induces apoptosis
in human retinal pigment epithelial (RPE) cells in diabetes. Reduction
of miR‐29 expression protects against the induced apoptosis by
hyperglycemia and reduces caspase‐7 protein production in RPE cells
(Lin et al., 2016). Moreover, it has been shown that miR‐29b
expression induction in neurons makes them escape from apoptosis
because miR‐29 induction controls the BH3‐only proteins, which are
the essential initiators of apoptosis (Kole et al., 2011). In addition,
lack of miR‐29 makes the brain neurons apoptosis (Roshan
et al., 2014).
2.3 | Muscle
miR‐29 stimulates muscle differentiation but suppresses the C2C12
myoblasts cell line into fibroblasts through targeting and suppressing
production of collagen and lims1. miR‐29 expression in C2C12
myogenic cell lines is reduced during muscles differentiation by
transforming growth factor β (TGF‐β). Furthermore, miR‐29 can
control TGF‐β through controlling Smad3 expression. The increasing
miR‐29 expression will suppress histone deacetylase 4 (HDAC4)
during translation in the presence or absence of TGF‐β (Winbanks
et al., 2011). miR‐29 in fibroblast colonies reduces the induced and
produced colonies by TGFβ1 and its expression through the negative
regulation of the wnt/β‐catenin pathway results in reduced collagen
expression (collagen type I α1 chain [COL1A1]; Tan et al., 2014). In
addition, cell treatment of human IMR‐90 cell line (fibroblast) with
TGF‐β1 reduces miR‐29 expression. Stimulation by TGF‐β1 increases
proliferation, colony production, and COL1A1 collagen expression.
However, miR‐29 expression reverses the effect of TGF‐β1 (Wang,
Liu, Chen, Feng, Guo, 2015).
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19282 | ALIZADEH ET AL.

T A B L E 1 Summary of some miR‐29 targets in maintenance of healthy tissues function

Tumor Target Function References
Immune system T‐bet, Eomes Suppression production of Steiner et al. (2011)
IFN‐γ in T helper cells
Immune system P40, IL‐23, ATF2 Negative regulation of IL‐23 Brain et al. (2013)
Immune system sST2 Decrease allergic inflammation Igarashi et al. (2018)
Apoptosis P85a, CDC42 Increase apoptosis through Park et al. (2009)
increase P53 expression
Apoptosis Mcl‐1 Increase apoptosis Mott et al. (2007)
Apoptosis c‐Jun Induce apoptosis Long et al. (2015)
Apoptosis Caspase‐7 Decrease apoptosis Lin et al. (2016)
Apoptosis BH3‐only proteins Decrease apoptosis Kole et al. (2011)
Myogenesis Lims1, collagen Suppression differentiation of C2C12 Winbanks et al. (2011)
myoblasts to fibroblasts
Myogenesis Wnt/β‐catenin pathway Decrease COL1A1 production through wnt/β‐ Tan et al. (2014)
catenin pathway
Myogenesis TGF‐β1 Decrease collagen production Wang, Liu, Chen, et al.
and proliferation (2015); Yang et al. (2013)
Myogenesis P85α, IGF‐1, B‐myb Increase atrophy Hu et al. (2014); J. Li
et al. (2017)
Myogenesis Tet1 Regulation of myoblast Chikenji et al. (2016)
production through upregulation of MyoD
and downregulation of Cdk6
Osteogenesis COL1A1, COL5A3, COL4A2, HDAC4, Osteoblasts differentiation and accumulation Li et al. (2009)
TGFβ3, ACVR2A, CTNNBIP1, DUSP2 of collagen proteins during mineralization of
bones
Osteogenesis Dkk1, sFRP2 Downregulation of Wnt signaling pathway Kapinas et al. (2010)
Osteogenesis DKK1 Bone loss with advancing age, increase Lee et al. (2017)
osteogenesis, and osteoblast potential
Osteogenesis Effective RNAs in cytoskeletal Upregulation of osteoclasts production Franceschetti et al. (2013);
organization Sudo et al. (2015)
ECM PI3K or AKT phosphorylation pathway Reduce COL1A1 expression Yang et al. (2013)
Intestine CDK2 Suppress growth of intestinal Xiao et al. (2013)
cells and mucosa growth
Intestine LRP6, HuR Regulation of cell growth and homeostasis Li et al. (2016)
thorough un‐stabilizing of Lrp6 and
HuR messenger RNAs
ESCs Tet1 Differentiation of ESCs and disturb ESCs Cui et al. (2016)
stabilization
HSPCs DNMT3a Increase the number of Hu et al. (2015)
HSPCs and HSC self‐renewal
Neurons Ireb2 Decrease delivery of iron to neurons Ripa et al. (2017)
DNA synthesis and Endogenous B‐Myb Suppress DNA synthesis and induce aging Martinez et al. (2011)
aging
Smooth muscle FBXO32, SMC Regulation of smooth muscle functions Cushing et al. (2015)
Lung Surfactant protein, SP‐A Reduce accumulation of Guo et al. (2016)
cAMP‐induced surfactant containing lamellar bodies
Note. ACVR2: activin A receptor type 2A; ATF2: activating transcription factor 2; cAMP: cyclic adenosine monophosphate; CDK2: cyclin‐dependent
kinase 2; COL1A1: collagen type I α1 chain; CTNNBIP1: catenin β interacting protein 1; Dkk1: dikkopf‐1; DNMT3a: DNA methyltransferase 3α; DUSP2:
dual specificity phosphatase 2; ECM : extracellular matrix; ESC: embryonic stem cell; HDAC4: histone deacetylase 4; HSC: hepatic stellate cell; HSPC:
hematopoietic stem and progenitor cell; IGF‐1: insulin‐like growth factor 1; IFN‐γ: interferon γ; FRP2: secreted frizzled‐related protein 2; LRP6: LDL
receptor‐related protein 6; SMC: smooth muscle cell; Tet1: ten‐eleven translocation enzyme‐1; TGF‐β3: transforming growth factor β3.

ALIZADEH ET AL.
miR‐29 significantly increases by the age increase in skeletal
muscles of mice. Increased miR‐29 expression inhibits the C2C12
myoblasts cell line proliferation and production of myotube. p85α,
insulin‐like growth factor 1 (IGF‐1), and B‐myb expression are
reduced by age increase, while the expression of the proteins
involved in cell cycle arrest, increases such as P53. Activating miR‐29
through Wnt‐3a suppresses these effective factors in myoblasts
proliferation by targeting p85α, IGF‐1, and B‐myb and results in
muscular atrophy and aging (Hu et al., 2014). In addition, miR‐29
leads to the muscular atrophy in C2C12 or initial myoblasts by
targeting IGF‐1 and PI3K‐(p85α) genes (J. Li et al., 2017). miR‐29a
inhibition in C2C12 myoblast cells lines increases ten‐eleven
translocation enzyme‐1 (Tet1). miR‐29a‐Tet1 path leads to the
positive regulation of MyoD and negative regulation of cyclin‐
dependent kinase 6 (Cdk6) and can play an important role in
myoblast cells regulating network. MyoD expression is increased by
inhabitation of Tet1 and decreased by suppressing miR‐29a, while
Cdk6 expression regulation is reverse (Chikenji et al., 2016).
2.4 | Skeleton
miR‐29a is essential for the differentiation of osteoblasts because its
expression level is increased in the differentiation process in the
initial culture of human osteoblasts. miR‐29b has an important role in
the differentiation of osteoblasts by various methods such as
increasing the COL1A1, COL5A3, and COL4A2 activity and
accumulates the collagen proteins accumulation in mineralization
step when miR‐29 reaches its peak. In addition, miR‐29b stimulates
osteogenesis through the negative regulation of inhibiting factors of
osteoblast differentiation such as HDAC4, TGFβ3, ACVR2A,
CTNNBIP1, and DUSP2 (Li et al., 2009). The suppression of
miR‐29a expression in osteoblast cells increases the osteonectin
protein level. Osteonectin is essential to stabilize bone mass and
balanced production of the bone in body skeleton. miR‐29a/c
expression is increased during the osteoblast differentiation and
their increase have a direct relationship with the osteonectin protein
reduction in matrix maturity and mineralization phases. Furthermore,
Wnt signaling pathway activity that is increased during osteoblast
differentiation expresses miR‐29 (Kapinas et al., 2009). miR‐29a is
the negative regulators of Wnt signaling pathway, and do it by
targeting the proteins of Dikkopf‐1 (Dkk1), Kremen2, and secreted
frizzled‐related protein 2 (sFRP2; Kapinas et al., 2009). In addition,
these antagonists were increased in cells with suppressed miR‐29a
expression. Wnt signaling pathway induces miR‐29 transcription,
then Wnt antagonist will have negative regulation and results in
reinforced Wnt signaling pathway (Kapinas et al., 2010). Increasing
IL‐32γ expression in transgenic mice reduces DKK1 expression
through positive regulation of miR‐29a, leads to bone loss with
advancing age, and increases skeleton production and osteoblasts
ability in comparison to the rats (Lee et al., 2017). Inhibition or the
lack of expression of miR‐29 leads to retrieved expression of elastin,
disruption in preosteoclasts, and osteoclastic commitment migration.
However, miR‐29 nonexpression does not influence cells viability,
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| 19283
actin ring production, and apoptosis of mature osteoclast. Thus, miR‐
29 is the positive regulator of osteoclast production and influence
osteoclast performance by targeting at the effective RNAs in
organizing cytoskeletal and commitment (Franceschetti et al., 2013).
2.5 | Extracellular matrix
miR‐29c has an important role in extracellular matrix production
such as seven types of collagen (COL4A1, COL4A2, COL3A1,
COL1A2, COL5A2, COL15A, and COL1A1), laminin‐γ1, fibrin, and
secreted proteins including acidic and cysteine‐rich (SPARK) ones
(Sengupta et al., 2008). Incubation of trabecular meshwork cells with
TGF‐β2 increases miR‐29a expression and suppresses miR‐29b.
However, it does not show any effect on miR‐29C from itself. miR‐
29 family has an important role in suppressing extracellular matrix
(ECM) proteins under the basal and TGF‐β2 stimulatory condition
(Villarreal et al., 2011). miR‐29 family expression reverses the effect
of TGFβ1 in the effective extracellular matrix synthesis. TGFβ1 uses
PI3k‐Akt pathway in embryonic fibroblasts, and miR‐29 family blocks
PI3K or AKT phosphorylation pathway and reduces COL1A1
expression (Yang et al., 2013).
miR‐29b expression in human trabecular meshwork cells negatively
regulates the existed compounds in ECM such as collagens (COL1A1,
COL1A2, COL4A1, COL5A1, COL5A2, and COL3A1), laminin γ1
(LAMC1), and fibrillin (FBN) as well as the other involved genes in
ECM deposition and remodeling such as SPARC/osteonectin (Luna
et al., 2009). It has been shown that glucocorticoids regulate Col3A1,
Col4A5, elastin (ELN), and matrix metallopeptidase 2 (MMP2)
expressions through miR‐29 induction and miR‐29C reduce Col3A1,
Col4A5, ELN, and MMP2 activity (Chuang et al., 2015). Inhibiting
miR‐29a expression using nanofibers in murine MC3T3‐E1 cell line can
increase osteonectin production. In addition, its inhibition in stromal
cells of bone marrow increases collagen production (James et al., 2014).
Increasing miR‐29a/b expression in hepatic stellate cells (HSC) reduces
collagen, type 1 and 4, synthesis, and stimulating by hepatocyte growth
hormone increases miR‐29 level intensity and suppresses collagen type
1 and 4 (Kwiecinski et al., 2011).
2.6 | Other biological processes
Increasing miR‐29b expression suppresses the growth of small intestine
mucosal cells by suppressing cyclin‐dependent kinase 2 (CDK2) and
cellular cycle arrest in GI step, and its nonexpression through increasing
CDK2 expression will increase intestine mucosal growth (Xiao et al.,
2013). Moreover, miR‐29b inhibits the LDL receptor‐related protein 6
(LRP6) and RNA‐binding protein HuR in epithelial cells of the intestine by
connecting to them through destabilization LRP6 and HuR mRNAs. Thus,
miR‐29b can regulate the proliferation and homeostasis of intestinal
epithelial cells by the stated process (Li et al., 2016).
miR‐29 family expression is increased in the initial steps of embryonic
stem cells (ESCs) differentiation, which indicates that miR‐29 effective
role in ESCs differentiation is processed by Tet1 inhibition. miR‐29 family
can suppress the Tet1 expression directly which plays a role in ESCs

19284 | ALIZADEH
stabilization (Cui et al., 2016). miR‐29a/b removal reduces the number of
hematopoietic stem and progenitor cells, HSC self‐renewal, and apoptosis
through the negative regulation of DNMT3a gene (Hu et al., 2015).
miR‐29 family expression has a reverse relationship with body iron
because miR‐29 family is connected to Ireb2 protein and reduces its
expression, so reduces iron delivery into neurons. miR‐29 family
expression is increased by increasing age and limits the extra contact
of iron with neurons by regulating extracellular iron hemostasis (Ripa
et al., 2017). miR‐29 family expression suppresses endogenous B‐Myb
and then inhibits DNA synthesis. Thus, the suppression of its expression
is tied to the aging process (Martinez et al., 2011). The lack of miR‐29
family expression in male mice led to an increase of their age but their
viability in female mice demonstrated reduction than rats (Takeda &
Tanabe, 2016). Moreover, miR‐29 family nonexpression in male mice
brain disturbs their fertility, while it reinforces the female mice fertility
(Takeda & Tanabe, 2016).
miR‐29 family is the most abundant miRNA in the mouse lung.
Increasing miR‐29 expression in vascular smooth muscle cells (vSMCs)
is observable in mouse and human pulmonary distal arteries, and the
lack of its expression increases FBXO32 expression. Therefore, miR‐29
plays a significant role in smooth muscles functions through reduction
of FBXO32 and SMC proteins (Cushing et al., 2015). miR‐29 family in
the isolated epithelial cells from mouse embryonic lung in late of
pregnancy or the isolated epithelial cells from human fetal lung (HFL)
explants during type II cell differentiation in culture was significantly
increased. miR‐29 family expression in the cultured epithelial cells of
the human lung is increased by cAMP but reduced by hypoxia. miR‐29
family nonexpression in HFL cells type 2, leads to nonexpression of SP‐
A and cAMP‐induced surfactant protein and nonaccumulation of
surfactant containing lamellar bodies. cAMP increases thyroid
transcription factor 1 (TTF‐1/Nkx2.1) connection to miR‐29a/b1
promoter in HFL type II cells (Guo et al., 2016). Later, TTF‐1 increases
miR‐29a/b1 promoter‐driven luciferase activity in cotransfection
F I G U R E 2 The role of miR‐29 family in the modulation of several human cancers development and progression [Color figure can be viewed
at wileyonlinelibrary.com]
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ET AL.
assays. Therefore, miR‐29 family as TTF‐1 driven, with SP‐A
expression mediator and type 2 cells differentiation acts by suppres-
sion of TGF‐β signaling (Guo et al., 2016).
3 | THE R OLE O F miR ‐2 9 F A M I LY I N
CAN CER
miR‐29 interaction with the target genes indicates its role in cells
growth, programmed death, differentiation, and proliferation and
confirms the direct function on cancer progression (Figure 2). miRNA
structure and their performance show that many miRNAs are
expressed in the cancerous samples nonnaturally. Genomic rearran-
gement, miRNA abnormalities or the involved proteins in their
construction, disruption in miRNA epigenetic regulation, and gene
mutations are the samples of changes, which express miRNAs in
cancers unnaturally (Schaefer et al., 2010; Table 2).
3.1 | Leukemia
miR‐29b retrieval in AML cells line, induced apoptosis, and reduced
tumorigenesis through apoptosis gene expression such as mantle cell
lymphoma 1 (MCL‐1; R. Garzon, Heaphy, et al., 2009a). miR‐29b is
suppressed in the patients with AML because of its defect in CCAAT/
enhancer‐binding protein‐a (CEBPA) performance or losing chromo-
some 7q. It has been indicated that CEBPA regulates miR‐29b
expression selectively on the 7q32.3 chromosome (Eyholzer et al.,
2010). miR‐29b expression in AML cells significantly reduces the
expression of DNA methyl transferases (DNMT) such as DNMT1,
DNMT3A, and DNMT3B at the RNA and protein level. DNMT3A and
DNMT3B expressions are reduced by miR‐29b direct connection to
their 3′‐untranslated region (3′‐UTR) area but reduce DNMT1
indirectly by targeting at specificity protein 1 (Sp1). Reduction in
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ALIZADEH ET AL. | 19285

T A B L E 2 Summary of some miR‐29 targets in several cancers therapy

Tumor Targets Function References
Leukemia (AML) MCL‐1, CCND2, Akt2, c‐Myc Increase apoptosis R. Garzon, Heaphy, et al.
(2009); J. N. Gong, Yu,
et al. (2014)
Leukemia (AML) Sp1, DNMT3A, DNMT3B Downregulation of DNMT1, decrease R. Garzon, Liu,
methylation, reexpression of cyclin‐ et al. (2009)
dependent kinase inhibitor 2B
(p15 INK4b) and ESR1
Leukemia (CML) BCR/ABL1, ABL1 Increase apoptosis Li et al. (2013)
Leukemia (ALL) BCL11B Increase apoptosis He et al. (2018)
Leukemia (CLL) Tcl1 Decrease aggressive, decrease methylation Pekarsky et al. (2010)
Breast cancer ADAM12‐L, B7‐H3, GATA3 Decrease metastasis Duhachek‐Muggy &
Zolkiewska, 2015);
Nygren et al. (2014)
Breast cancer TIMP3 Decrease metastasis Chou et al. (2013);
through TIMP3/STAT1/FOXO1 pathway Duhachek‐Muggy &
Zolkiewska, 2015)
Breast cancer NMI Increase metastasis Rostas et al. (2014)
Breast cancer P38‐STAT1 pathway Decrease metastasis, cell Liu et al. (2017)
growth and drug resistance
through suppression of p38‐STAT1 pathway
Breast cancer CDC42, B‐Myb Arrest cell cycle Zhang et al. (2016)
Breast cancer ERK Increase metastasis through ERK Z. Li et al. (2017)
phosphorylation
Breast cancer SPINDLIN1 Decrease cell growth Drago‐Ferrante
et al. (2017)
Hepatocellular carcinoma TET, CLDN1 Decrease metastasis and proliferation Mahati et al. (2017)
Hepatocellular carcinoma RPS15A, IGF2BP1 Increase apoptosis and inhibit Yang et al. (2018)
cells proliferation
Hepatocellular carcinoma Bcl‐2, Mcl‐1, cytochrome c Increase apoptosis Xiong et al. (2010)
Hepatocellular carcinoma Cyclin A, cyclin D1, P21 Control cell cycle N. S. Zhang et al. (2017)
Hepatocellular carcinoma SIRT1 Suppress cell growth through pRb Bae et al. (2014)
hypophosphorylation
Hepatocellular carcinoma WIP1 Suppress P53 pathway B. Wang et al. (2015)
Ovary cancer BAG Increase apoptosis through negative Sugio et al. (2014)
regulation of Mcl‐1
Ovary cancer MMP2 Decrease metastasis Li et al. (2015)
Ovary cancer AKT2/AKT3 Decrease cancerous cell growth through Teng et al. (2015)
negative regulation of HK2/PKM2 and
reduced Warburg effect
Ovary cancer DNMT3A, DNMT3B Decrease methylation Creighton et al. (2012)
Gastric cancer Mcl‐1, RCC2, ITGB1 Suppress cancerous cells through inhibition of Han et al. (2015); Matsuo
differentiation, metastasis, and increase et al. (2013); Saito
apoptosis et al. (2013)
Gastric cancer DNMT3A Decrease methylation Cui et al. (2015)
Gastric cancer CTNND1, hyaluronan synthase 3, Suppress tumor and metastasis F. Bai et al. (2018); J.
CCND2, MMP2, P42.3 Gong, Li, et al. (2014);
Y. Wang et al. (2015)
Melanoma CDK6 Arrest cell cycle Schmitt et al. (2012)
Melanoma DNMT3A, DNMT3B Decrease methylation Nguyen et al. (2011)
Melanoma LAMC1, PPIC Decrease metastasis Andrews et al. (2016)
Colon cancer BCL9L, CDC42BPA, BAIAP2, Decrease metastasis and proliferation He et al. (2017);
(Continues)
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19286 | ALIZADEH ET AL.

TABLE 2 (Continued)

Tumor Targets Function References

TIAM1, IQGAP2, PHLDB2, SSH1, Subramanian et al.
SPARC, P53 (2014); S. Zhang
et al. (2017)
Colon cancer KLF4 Increase metastasis through MMP2/E‐ Tang et al. (2014)
cadherin regulation
Lung cancer FHIT, WWOX, DNMT3A/3B Decrease tumorigenesis Fabbri et al. (2007)
Lung cancer LOXL2 Suppress metastases and invasions MIZUNO et al. (2016)
Lung cancer WIF‐1 Increase apoptosis through Wnt/β‐catenin Molina et al. (2008)
signaling pathway
Lung cancer Mcl‐1, Bcl‐2 Increase apoptosis Arechaga‐Ocampo
et al. (2017)
Pancreatic cancer ATG9A, TFEB Increase the effect of gemcitabine in cancer Kwon et al. (2016)
cells and decrease invasion
Pancreatic cancer MUC1, MUC16 Decrease tumorigenesis Tréhoux et al. (2015)
Pancreatic cancer MMP2 Decrease tumorigenesis and metastasis Zou et al. (2015)
Pancreatic cancer DNMT3b Decrease methylation Wang et al. (2018)
Glioblastoma Podoplanin Increase apoptosis Cortez et al. (2010)
Glioblastoma COL1A2, COL3A1, COL4A1, ELN, Increase apoptosis, decrease MMP‐2 activity Shin et al. (2017)
ITGA11, MMP24, SPARC, through phospho‐AKT/β‐catenin signaling
Phospho‐AKT/β‐catenin signaling pathway, suppress angiogenesis through
pathway, VEGF, Ang‐2, BCL2L2 reduction of VEGF and Ang‐2 expression
Glioblastoma QKI‐6 Decrease tumorigenesis and metastasis and Xi et al. (2017)
induce apoptosis through suppression of
WTAP expression, phosphoinositide 3‐kinase/
AKT and extracellular signal‐related kinase
pathways
Glioblastoma DNMT3A/3B Decrease methylation Xu et al. (2015)
Glioma CDC42 Decrease tumorigenesis and metastasis Shi et al. (2017
through reduction of phosphorylated PAK1/
2/3, LIMK1/2, and cofilin
Glioma Sp1 Increase chemotherapy effect through Xiao et al. (2016)
suppression of MGMT
Glioma MYCN Decrease tumorigenesis Sun et al. (2017)
Lymphoma CDK6, DNMT3B, TCL1, MCL‐1, Decrease tumorigenesis, metastasis, and Kohnken et al. (2018);
BRD4, DNMT1 methylation Robaina et al. (2015);
Zhao et al. (2010)
Osteosarcoma Bcl‐2, Mcl‐1, E2F1, E2F3 Decrease tumorigenesis W. Zhang et al. (2012)
Osteosarcoma MCL1 Increase chemotherapy effect and apoptosis Osaki et al. (2016)
Prostate cancer Mcl‐1, COL1A1, COL4A1, MMP‐2 Decrease tumorigenesis Steele et al. (2010)
Prostate cancer Collagen Decrease metastasis Ivanovic et al. (2018)
Prostate cancer LAMC1, LOXL2 Decrease tumorigenesis and metastasis Nishikawa et al. (2014)
Cervix cancer YY1, CDK6 Induce apoptosis Li et al. (2011)
Rhabdomyosarcoma NF‐κB–YY1 pathway Decrease tumorigenesis Grifoni & Maher, 2016)
Oral cancer CDK6 Decrease tumorigenesis L. Chen et al. (2017)
Neuroblastoma, B7‐H3 Suppression of tumorigenesis, metastasis, and Purvis et al. (2018)
medulloblastoma, sarcomas and angiogenesis
brain tumor
Note. ADAM12‐L: A disintegrin and metalloproteinase 12; AML: acute myeloid leukemia; BAG: Bcl2‐associated athanogene; CLDN1: claudin‐1; CLL:
chronic lymphocytic leukemia; CML: chronic myeloid leukemia; DNMT: DNA methyl transferase; ESR1: estrogen receptor 1; ITGB1: integrin β1; LOXL2:
lysyl oxidase‐like 2; MCL: mantle cell lymphoma; MGMT: O6‐methylguanine‐DNA methyltransferase; MMP2: matrix metalloproteinase 2; MUC1: mucin
1; NF‐κB: nuclear factor κB; NMI: N‐myc interactor; PPIC: peptidyl‐prolyl cis‐trans isomerase C; QKI‐6: quaking gene isoform 6; RCC2: regulator of
chromosome condensation 2; Sp1: specificity protein 1; TCL1: T‐cell leukemia protein 1; TIMP3: TIMP metallopeptidase inhibitor 3; VEGF: vascular
endothelial growth factor; WIF‐1: Wnt inhibitory factor‐1; WIP1: wild‐type p53‐induced phosphatase 1; WTAP: Wilms tumor 1‐associated protein.

ALIZADEH ET AL.
DNA methylation re‐expresses the cyclin‐dependent kinase inhibitor
2B (p15 INK4b) and estrogen receptor 1 genes which were
methylated because of cancerous cells (R. Garzon, Liu, et al.,
2009b). Reduction of miR‐29 expression is seen more in AML than
CML, in a way that decline of miR‐29a expression can be utilized as a
diagnostic factor in peripheral blood mononuclear cells of AML
patients (Xu et al., 2014).
miR‐29 family in peripheral blood mononuclear cells and CD34+
cells of bone marrow are reduced in patients with AML. miR‐29 family
has the potential to repress cancer by regulation of cell proliferation
and apoptosis through targeting mRNAs, CCND2, and AKT2. Reduc-
tion of miR‐29 family expression increases Akt2, CCND2, and c‐Myc in
AML and finally worsens cancer (J. N. Gong, Yu, et al., 2014). miR‐29c
is increased in patients with AML and increasing its expression is the
danger factor to relapse after achieving complete remission. miR‐29c
can be used as a prognostic indicator. In addition, the low level of
miR‐29c helps to improve the treatment process in old patients
treated by azacitidine (Butrym et al., 2016). miR‐29a/b expression is
declined intensively in CML, which can result in increased expression
of two of their target genes, Bcl‐2 and Mcl‐1 in the peripheral blood
mononuclear cells (Xu et al., 2014). miR‐29b expression is reduced in
this cancer type and through negative regulation of BCR/ABL1 and
ABL1 proteins induces apoptosis in AML cells (Li et al., 2013).
miR‐29a level in T cancerous cells is significantly reduced in ALL
than normal T cells. In addition, miR‐29a level reduction increases the
number of blasts in bone marrow. The re‐expression of miR‐29a in
Jurkat and Molt‐4 T‐ALL cells demethylated genes, which were
methylated for being cancerous (Oliveira et al., 2015). miR‐29a
suppresses BCL11B and probably reduction of miR‐29a in ALL is for
the positive regulation of BCL11B. BCL11B is highly expressed in
ALL, and its negative regulation inhibits the proliferation and
induction of apoptosis in T‐ALL cells (He et al., 2018). However,
the increased expression of miR‐29c in TAL‐R subtype of ALL (TAL‐R
T‐ALLs) was seen in comparison to CD4+ CD8+ cells (Wallaert et al.,
2017). Reduction of miR‐29 expression increases T‐cell leukemia
protein 1 (TCL1) production that is a needed molecule for chronic
lymphocytic leukemia (CLL) aggressive pathogenesis and reduces
DNA methylation by suppression of DNMT3A and DNMT3B
expression. However, as TCL1 is relatively not expressed in indolent
B‐CLL, its expression reduction by increasing miR‐29 in this CLL type
has no important role in indolent B‐CLL. The defect in miR‐29
regulation can help the pathogenesis of indolent B‐CLL, and its
expression is increased in this CLL type. Actually, miR‐29 has
expression increase in both types of indolent and aggressive CLL
than normal B cells (Pekarsky et al., 2010). miR‐29a/c is one of five
miRNAs with the maximum expression in CLL (Zanette et al., 2007).
Nonetheless, miR‐29 expression in CLL patients is reduced for whom
the P53 gene is reduced or mutated (Mraz et al., 2009).
3.2 | Breast cancer
miR‐29 in serum and tissue of patients with breast cancer was seen
more than the ones for the healthy people and this feature is used to
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| 19287
diagnose this disease in infected patients (Shaker et al., 2015).
Studying A disintegrin and metalloproteinase 12 (ADAM12‐L),
mRNA, and B7‐H3 can be helpful to the diagnosis and prognosis of
breast cancer (Duhachek‐Muggy & Zolkiewska, 2015). GATA3 is
removed in breast cancer and is associated with weak prognosis in
patients. GATA3 as a transcription factor suppresses metastasis and
changes tumor surrounding using induction of miR‐29b expression
(Chou et al., 2013). ADAM12‐L and B7‐H3 are increased in breast
cancer, however, ADAM12‐L 3′‐UTR is the main target of miR‐29;
and miR‐29b/c mimics transfection significantly reduces ADAM12‐L
mRNA level in SUM159PT and BT549 cell (Duhachek‐Muggy &
Zolkiewska, 2015) and B7‐H3 is an immunity regulator protein that is
expressed in cancers extremely and induces weak metastasis and
prognosis. MiR‐29c is connected to 3′‐UTR B7‐H3 area and reduces
its expression. The direct relationship between miR‐29c increase and
the cased death reduction by breast cancer was observed in cohort
research (Nygren et al., 2014). Reduction of miR‐29c expression
increases DNMT3B expression. This upregulation can increase the
methylation of TIMP‐metallopeptidase inhibitor 3 (TIMP3) promoter.
As a result, it reduces TIMP3 expression that stimulates breast
cancer progress by TIMP3/STAT1/FOXO1 pathway. Thus, miR‐29c
can be used as a diagnosis and medical biomarker of breast cancer
(Duhachek‐Muggy & Zolkiewska, 2015). miR‐29 plays a role in
invasion or metastasis of cancerous cells by using of N‐myc
interactor (NMI) expression reduction. miR‐29 improper expression
may reduce NMI expression in breast cancer that can lead to an
invasion and metastasis of cancer (Rostas et al., 2014).
Increasing miR‐29b expression in the activated fibroblasts
through suppressing p38‐STAT1 signaling path can suppress cell
growth, drug resistance, and metastasis in breast cancer. In addition,
its nonexpression is tied to cell growth, drug resistance, and
metastasis (Liu et al., 2017). miR‐29a arrests cell cycle by using the
negative CDC42 regulations and B‐Myb downregulation that is a
related transcription factor to tumorigenesis (Zhang et al., 2016).
However, miR‐29a can increase proliferation and invasion of cells.
Human insulin can increase miR‐29a expression in estrogen receptor‐
positive breast cancer cells and then increases insulin, which raises
insulin effect that grows up the cells proliferation and migration.
Furthermore, miR‐29a accelerates cells proliferation and metastasis
using ERK phosphorylation (Z. Li et al., 2017). Declined expression of
miR‐29b is observed in tissue and cells of triple negative breast
cancer (TNBC), which is the most invasive type of breast cancer. The
increased miR‐29b ectopic expression will reduce the cellular growth
of TNBC, migration, self‐renewal, and miR‐29b can directly control
SPINDLIN1 (SPIN1) that is extremely expressed in TNBC cells and
tissues (Drago‐Ferrante et al., 2017).
3.3 | Hepatocellular carcinoma (HCC)
miR‐29 family expression indicates a significant reduction in liver
cancer, and this reduction leads to progressive disease and declines the
patients living chance. Reduced expression of miR‐29a will increase
claudin‐1 (CLDN1). CLDN1 is a cancerous factor and plays a role in

19288 | ALIZADEH
metastasis (Mahati et al., 2017). Declined expression of miR‐29 will
increase ten‐eleven translocations (TET) expression which plays role in
invasion, migration, and proliferation of liver cancer cells in a way that
the negative regulation of miR‐29 makes tumor and disease progress
through reinforcing TET1 expression (Lin et al., 2014). TET enzymes
change 5‐methylcytosine to 5‐hydroxymethylcytosine and play im-
portant roles in biological processes through demethylation of DNA.
miR‐29 reduces the mRNAs expression of TET1 enzyme by direct
connection to 3′‐UTR (Q. Chen et al., 2017).
miR‐29 family inhibits the cells proliferation and tissue of the
liver cancer and induces apoptosis in cells through targeting 3′‐UTR
area of RPS15A gene and reduction of its expression. miR‐29 family
expression is reduced in cells and tissues of liver cancer, and the
increase of this family expression in liver cancer cells controls the
cells proliferation and induces the apoptosis by targeting various
genes including insulin‐like growth factor 2 binding protein 1
(IGF2BP1; Yang et al., 2018). Increased miR‐29 expression disturbs
mitochondrial function by the loss of cytochrome c into the
cytoplasm and leads to cell apoptosis through involving Bcl‐2 and
Mcl‐1 genes (Xiong et al., 2010). Cyclin A, cyclin D1, and p21 genes
that are tied to cell cycle control are reduced by miR‐29 family (N. S.
Zhang et al., 2017).
miR‐29c suppresses liver cancer cells through suppressing
mammalian sirtuin 1 (SIRT1) which is effective in energy metabolism
and tumorigenesis. SIRT1 suppresses liver cancer cells by the
negative regulation of cell cycle proteins. SIRT1 nonexpression
hypophosphorylates pRb, which inactivates its targeted gene
transcription, E2F/DP1. Finally, it arrests the cell cycle in G1/S
phase (Bae et al., 2014). Moreover, miR‐29c expression reduction
increases the expression of wild‐type p53‐induced phosphatase 1
(WIP1) with the controlling role in several suppressing pathways for
tumor growth such as P53 (B. Wang et al., 2015). If α‐fetoprotein
(AFP) is expressed in the negative AFP cells of HCC, the proliferation
and invasion of HCC cells will increase. The high expression of AFP
controls miR‐29a expression. AFP inhibits the Lucas transcription of
miR‐29a/b by c‐MYC connection and reduces its expression to 50%
(Parpart et al., 2014). Moreover, increasing the expression of
eukaryotic initiation factor 5A2 (EIF5A2) in HCC cells connects
c‐Myc to miR‐29b promotor and leads to its negative regulation
which can result in metastasis. This study showed that EIF5A2 helps
to CD133+ HCC cells stabilization through c‐Myc/miR‐29b axis
(H.‐Y Bai et al., 2018).
3.4 | Ovarian cancer
miR‐29b expression is reduced in ovarian cancer and its increase has
a direct relationship with the increase of the patients’ viability. In
addition, miR‐29 expression is reduced in patients who are in the
postmenopausal phase (Flavin et al., 2009). Bcl2‐associated athano-
gene (BAG) gene is not expressed because increasing miR‐29b
expression will regulate Mcl‐1 gene negatively and leads to the cell
apoptosis (Sugio et al., 2014). Increasing Mcl‐1 expression reduces
MMP‐2 expression and controls metastasis in OVCAR‑3 cells
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ET AL.
(Li et al., 2015). miR‐29b reduces cancer growth speed in ovarian
epithelial cells by the negative regulation of AKT2/AKT3 expression,
then the negative regulations of HK2/PKM2, and finally reduction of
Warburg effect (Teng et al., 2015). Increasing of miR‐29a expression
by suppressing several genes including DNMT3A and DNMT3B will
reduce the stability of the cancerous cells, and increasing its
expression is tied to the cell growth inhibition of OvCar‐8 and
HEYA8 cell lines (Creighton et al., 2012; Nymoen et al., 2016).
3.5 | Gastric cancer
miR‐29c shows its suppressing activity in gastrointestinal cancer by
different mechanisms such as suppressing the Mcl‐1 antiapoptosis
protein (Saito et al., 2013), reducing regulator of chromosome
condensation 2 gene regulation (Matsuo et al., 2013) and targeting
integrin β1, which has a role in differentiation, migration, and
apoptosis (Han et al., 2015). miR‐29c is reduced in the cancerous
tissue of the gastrointestinal system, and its expression depends on
tumor size, metastasis to lymph nodes, and the clinical stage of
cancer (Ma et al., 2013). Therefore, its measurement can be used as
an index for the prognosis of this cancer type (Ma et al., 2013).
DNMT3A gene is the target of miR‐29b/c and suppresses it.
Moreover, DNMT3A is enabled to induce miR‐29b/c suppression in
a DNA methylation‐dependent manner. The lack of expression of
miR‐29b/c leads to the silence of the epigenetic dependent CDH1
gene and metastasis in this cancer type (Cui et al., 2015). miR‐29s
prevent metastasis and invasion of gastrointestinal cancer by
targeting catenin‐δ as a metastasis suppressor (Y. Wang et al.,
2015) and miR‐29a by the negative regulation of hyaluronan
synthase 3 expressions (F. Bai et al., 2018). Furthermore, miR‐29
family suppresses gastrointestinal tumor through targeting CCND2,
MMP2 genes, p42.3 in protein level, and mRNA that plays roles in the
proliferation of cancerous cells (J. Gong, Li, et al., 2014; Y. Wang
et al., 2015).
3.6 | Melanoma
Increased miR‐29a/b in melanoma cancer cells reduces CFK6
expression and finally reduces their proliferation power. miR‐29a/b
can reduce CDK6 expression in mRNA and protein level, which plays
a role in transferring from G1/S phase in the cell cycle. The amount of
miR‐29a/b expression was increased a little in metastatic cells of
melanoma in two out of five patients in which can be the result of
reducing IFN‐γ signaling pathway in them. IFN‐γ increases miR‐29
expression though dependence on STAT1 pathway. On the contrary,
increased miR‐29 expression results in downregulation of IFN‐γ
expression through targeting of its transcription activators such as
T‐bet and Eomes (Schmitt et al., 2012). miR‐29c expression is
correlated with the progression of the stages of melanoma (AJCC
stages) and is reduced in four stages of AJCC. Furthermore, miR‐29c
expression shows the reverse correlation with the expression of
DNMT3A and DNMT3B proteins (Nguyen et al., 2011). Cell
treatment with miR‐29b mimics reduces the transcription abundance

ALIZADEH ET AL.
of LAMC1, peptidyl‐prolyl cis‐trans isomerase C, and modest effects
and controls the metastasis of melanoma (Andrews et al., 2016).
3.7 | Colon cancer
miR‐29b can be used as a method for prognosis of colon cancer
because its amount is reduced in this cancer type (Basati et al., 2016).
miR‐29b declines the growth and invasion of colon cancer cells. This
process happens even in the absence of P53 and thorough
suppressing of β‐catenin/Wnt signaling pathway, which plays an
important role in the pathogenesis of colon carcinoma and results in
reduced expression of coactivators of β‐catenin in SW480 cells.
Moreover, β‐catenin translocation is reduced by connecting the miR‐
29b to 3′‐UTR of BCL9L mRNA (Subramanian et al., 2014).
miR‐29a results in migration and invasion of the colon cancerous
cells and positive regulations of CDC42BPA, BAIAP2, and TIAM1. The
silencing of the CDC42BPA gene reduces the effect of miR‐29a in
controlling the invasion and migration of cells. Moreover, increasing
the expression of IQGAP2, PHLDB2, and SSH1 and negative
regulations of PAK1 are observed by suppressing miR‐29a. miR‐29a
expression is reduced by disease progression and its suppression
causes metastasis (He et al., 2017). It has been indicated in another
research that increasing miR‐29a expression stimulates metastasis in
colon cancer as this process happens using the MMP2/E‐cadherin
regulation and through targeting KLF4 (Tang et al., 2014). Further-
more, studies have shown that miR‐29c expression is reduced in colon
cancer and its increased expression will control the migration and
proliferation of the cells. SPARC and P53 genes are targeted by miR‐
29c and their silence leads to cancer metastasis and invasion, which
reduces the patient’s viability (G. Chen, Zhou, Li, Yu, & Sun, 2017; S.
Zhang, Jin, Tian, & Wu, 2017)
3.8 | Lung cancer
miR‐29 was reduced in 77% of patients and its high amount of
expression in patients increased their viability and the effect of
chemotherapy for cisplatin in patients with resistance to cisplatin.
miR‐29c increases the cisplatin effect through the negative regulations
of the PI3K/Akt pathway (Sun et al., 2018). Increased miR‐29 expression
in non‐small‐cell lung cancer (NSCLC) leads to retrieving of the natural
pattern of DNA methylation and induction of the tumor suppressive
genes such as FHIT and WWOX, which is associated with inhibited
tumorigenesis. Increasing of miR‐29 expression reduces DNMT3A/3B
expression in lung cancer tissue (Fabbri et al., 2007). Lysyl oxidase‐like 2
(LOXL2) gene is regulated by miR‐29 and its extreme expression is seen
in lung cancer. Retrieving miR‐29 reduces LOXL2 in a way that LOXL2
arrest, suppresses the migration and invasion of lung cancer cells
(Mizuno et al., 2016).
miR‐29a acts as a tumor suppressor and is tied to expression
reduction in this type of cancer (H. Y. Wang et al., 2015). Losing of miR‐29
increases invasion in lung cancer. As it has been shown, miR‐29
expression is reduced in high‐metastatic NSCLC, and this reduction
increases metastasis in low‐metastatic NSCLC (H.Y. Wang et al., 2015).
10974652, 2019, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jcp.28607 by Universitat De Valencia, Wiley Online Library on [30/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
| 19289
miR‐29 suppresses Wnt inhibitory factor‐1 (WIF‐1) signaling pathway
through WIF‐1 demethylation in NSCLC. miR‐29 increases WIF‐1
expression through suppressing of promoter methylation and controls
Wnt/β‐catenin signaling pathway. Finally, it results in suppressed cells
proliferation and apoptosis (Molina et al., 2008). miR‐29c expression in
the resistant Calu‐1 cells to radiotherapy copes with their resistance by
apoptosis activation and the negative regulation of Bcl‐2 and Mcl‐1.
Moreover, reduction of miR‐29c expression has a direct relationship with
the caused viability by radiotherapy (Arechaga‐Ocampo et al., 2017).
3.9 | Pancreatic cancer
Reduction of miR‐29 expression is observed in pancreatic cancerous
cells and its expression retrieval suppresses cancer and reduces the
viability and migration (Factora et al., 2018). MYC plays an important
role in miR‐29 regulation in pancreatic cancer and the lack of its
expression increases the double expression of miR‐29 (Kwon et al.,
2018). miR‐29a is reduced in pancreatic ductal adenocarcinoma
(PDAC) and acts as a suppressor of autophagy by reducing the
autophagy proteins such as TFEB and ATG9A. Furthermore, its
expression can increase the gemcitabine effect on cancerous cells
and leads to the reduction of metastasis (Kwon et al., 2016). The
strong suppressor for mucin 1 (MUC1) is oncogenic mucin that copes
with the pancreatic cancerous cells with MUC16‐mediated migration
and invasion. MUC16 regulates c‐Myc positively and suppresses miR‐
29a expression. miR‐29a expression has a reverse relationship with
MUC16 expression (Tréhoux et al., 2015).
TGF‐β suppresses miR‐29c expression and increases Wnt cascade
activity which followed by tumorigenesis. miR‐29c reduces Wnt
waterfall activity by its suppressing effect on its regulators (Jiang
et al., 2015). Lack of miR‐29 expression was observed in pancreatic
stellate cells/fibroblasts cells, which are the main stromal cells and
responsible for fibrotic stroma reaction. Lack of miR‐29 is associated
with the increase of extracellular matrix, which has a significant role
in PDAC. Increasing of miR‐29 expression in active stellate cells
reduces stromal accumulation, the stability of the cancer cell, and
their growth (Kwon et al., 2015). miR‐29c reduces MMP2 expression,
which is increased in pancreatic cancer by targeting it and leads to
suppressed migration and metastasis (Zou et al., 2015). Furthermore,
the decline of miR‐29b expression can be observed in pancreatic
cancer, and it is demonstrated that its expression has a reverse
relationship with the DNMT3b expression. miR‐29b increased
expression influences the cancerous cells and caused increasing of
the cells apoptosis through targeting DNMT3b (Wang et al., 2018).
3.10 | Glioblastoma
miR‐29b expression is reduced in glioblastoma cells and inhibits the
cells apoptosis and proliferation by reducing podoplanin gene
expression, which has a role in cells invasion (Cortez et al., 2010).
The signaling pathway of epidermal growth factor receptor in
glioblastoma cells improves miR‐29 expression by the positive
regulation of SCAP/SREBP‐1, and sterol regulatory element binding

19290 | ALIZADEH
protein 1 (SREBP‐1) activates miR‐29 promoter by connecting to its
promotor and finally, it suppresses lipid synthesis and cell growth in
glioblastoma. In contrary, miR‐29 suppresses SREBP cleavage‐
activating protein (SCAP) and SREBP‐1 expression (Ru et al., 2017).
miR‐29b can be effective in suppression and apoptosis of glioblas-
toma cells by inhibiting the expression of COL1A2, COL3A1,
COL4A1, ELN, ITGA11, MMP24, and SPARC, reducing MMP‐2
activity by phospho‐AKT/β‐catenin signaling pathway, and suppres-
sion of angiogenesis by weakening vascular endothelial growth factor
and Ang‐2 expression (Shin et al., 2017).
miR‐29a declines Quaking gene isoform 6 (QKI‐6) expression
through linkage to it and leads to suppressed metastasis of the
glioblastoma stem cells (GSCs). Increased miR‐29a expression in
GSCs results in inhibited Wilms tumor 1‐associated protein expres-
sion, suppressed phosphoinositide 3‐kinase/AKT and extracellular
signal‐related kinase pathways through negative regulation of QKI‐6,
and eventually inhibits migration, proliferation, and invasion and
induces apoptosis (Xi et al., 2017). Moreover, miR‐29 family reduces
the expression of DNMT3A/3B thorough downregulation of them in
U87MG glioblastoma cell lines and leads to reduced hypermethyla-
tion in U87MG cells (Xu et al., 2015).
3.11 | Glioma
miR‐29 family can be measured as the detection index to detect and
screen the infected patients to the progressed form of glioma
because its expression in acute stages of the disease is more than the
initial stage of disease (Wu et al., 2015). miR‐29 expression has a
positive correlation with the patients’ viability and increased
expression of it leads to reduced migration and metastasis through
targeting of CDC42, which be followed by phosphorylated PAK1/2/3,
LIMK1/2, and cofilin reduction (Shi et al., 2017). DNA repairing
protein, O6‐methylguanine‐DNA methyltransferase (MGMT), has an
important role in glioma cells resistance to temozolomide. miR‐29c
can suppress MGMT by targeting Sp1 and this method can be used to
increase the therapeutic effect of chemotherapy (Xiao et al., 2016).
Furthermore, miR‐29b controls glioma cells proliferation by MYCN
targeting, and it can be used as a disease detection marker (Sun
et al., 2017).
3.12 | Lymphoma
miR‐29a/b/c expression is related with the prognosis of MCL in a
way that patients with low expression of miR‐29a/b/c have shorter
viability. Therefore, miR‐29 can be used as a detection marker
(Zhao et al., 2010). Decitabine improves miR‐29 expression.
Improved miR‐29 expression reduces CDK6, DNMT3B, TCL1,
MCL‐1, and BRD4 protein levels in Burkitt’s lymphoma (Kohnken
et al., 2018; Robaina et al., 2015; Zhao et al., 2010). miR‐29 inhibits
metastasis through the suppression of DNMT3B and DNMT1
expression. DNMT1 and DNMT3B expression are increased in
Burkitt’s lymphoma and their reduced expression results in
inhibited cells growth (Robaina et al., 2015). Tumors with the lack
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ET AL.
of MYC, indicate higher rates of miR‐29 expression because miR‐29
is suppressed by MYC through a corepressor complex by HDAC3
and EZH2. Inhibited HDAC3 and EZH2 results in disturbed MYC‐
EZH2‐miR‐29 axis. As a result, miR‐29 expression is retrieved and
leads to downregulation of its target genes and suppressed
lymphoma growth (Mazzoccoli et al., 2018; X. Zhang et al., 2012).
3.13 | Osteosarcoma
miRNA‐29a/b expression was reduced in the involved tissues with
osteosarcoma (23 out of 30 patients). miR‐29a can make apoptosis in
U2OS and SAOS‐2 cell lines by reducing Ncl‐2 and Mcl‐1 expression
and increasing two tumor suppressor genes include E2F1 and E2F3
(W. Zhang et al., 2012). OBP‐301 (stromelysin) increases miR‐29
expression through increasing E2F1 transcription factor activity.
Later, MCL‐1 expression is reduced, and the chemotherapy effect is
improved during the apoptosis of the osteosarcoma cells (Osaki et al.,
2016). miR‐29b can be used as an index for the prognosis of cancer;
miR‐29 expression is reduced more by increasing tumor size and
progress. In addition, patients with reduced miR‐29 expression have
shorter viability. Measuring miR‐29a/b can be used for the disease
prognosis; however, higher miR‐29c levels in osteosarcoma do not
have a relationship with disease symptoms and prognosis (Hong
et al., 2014).
3.14 | Prostate cancer
C‐myc promoter binding protein‐1 reduces tumor growth by increas-
ing five to nine times more of miR‐29b expression. miR‐29b can
suppress prostate cancerous cells by inhibiting Mcl‐1, COL1A1,
COL4A1, and MMP‐2 (Steele et al., 2010). The increasing of miR‐
29b expression reduces metastasis by reducing collagen expression
(Ivanovic et al., 2018). MiR‐29 in PC3 and DI14 cells inhibits the
invasion and migration of cancerous cells by direct regulation and
silencing of LAMC1 genes (Nishikawa et al., 2014). Moreover, miR‐29
suppresses the expression of lysyl oxidase‐like 2 (LOXL2) gene in
prostate cells. LOXL2 expression in prostate cancer cells is increased
and the lack of its expression can inhibit the migration and invasion of
the cells (Kato et al., 2017). Androgen receptor (AR) can decline the
stability and migration of the cancerous cells and induce apoptosis
thorough stimulating of miR‐29a expression which indicates the
regulation effect of androgen on miR‐29a (Pasqualini et al., 2015). In
contrary, circular RNA myosin light chain kinase progresses cancer by
reducing of Mir‐29a expression (Dai et al., 2018).
3.15 | Other Cancers
Retrieving miR‐29a expression in cervical cancer cells demonstrates
that this miRNA can inhibit cellular invasion and migration
(Yamamoto et al., 2013). Increasing of miR‐29b expression
suppresses the invasion and angiogenesis and suppresses tumor
growth by targeting STAT3 signaling pathway as the chemotherapy
by cisplatin will suppress angiogenesis of the cancerous cells

ALIZADEH ET AL.
proliferation through miR‐29b/STAT3 axis (Y. Li et al., 2017).
Moreover, miR‐29 cause apoptosis in cervical cancer cells, which
made malignant by human papillomavirus (HPV) through targeting
at YY1 and CDK6 in cervical cancer cells that became malignant by
HPV (Li et al., 2011). In addition to this, nuclear factor‐κB (NF‐κB) is
active in myoblast and makes myogenic differentiation through the
negative regulation of YY1 and miR‐29 (Grifoni & Maher, 2016).
miR‐29 expression is reduced by activating of NF‐kB–YY1 pathway
in rhabdomyosarcoma cells with defects in their differentiation
(Grifoni & Maher, 2016).
Leukoplakia and lichen planus are precancerous lesions, and miR‐
29 expression is reduced in leukoplakia and cancerous tissue but
increased in lichen planus tissue. Thus, lichen planus can be
differentiated from healthy tissue by miR‐29 measurement (Roy
et al., 2016). miR‐29c expression is increased in oral squamous cell
carcinomas (OSCC), which have the maximum invasion and metas-
tasis, then it can be used as the detection marker (Lopes et al., 2018).
Moreover, miR‐29 can reduce OSCC cells proliferation by reducing
CDK6 expression (L. Chen et al., 2017). miR‐29a/b/c expression is
reduced in solid tumors such as neuroblastoma, medulloblastoma,
sarcomas, and brain tumors. miR‐29 expression has a reverse
relationship with B7‐H3 expression. So that, increasing of miR‐29
expression will reduce B7‐H3 expression. miR‐29 suppresses
angiogenesis, migration, and invasion in solid tumors by reducing
B7‐H3 expression (Purvis et al., 2018).
4 | miRNA AN D C ANC ER
miRNA interaction with the target genes confirms their role in growth,
programmed death, differentiation, and cellular proliferation, and the
direct role of miRNA. The differences between miRNAs expression in
various cancers can be caused by the differences of the cancerous cell
origin and its surrounding stromal tissue. Changing of miRNA
expression will lead to a tumor by reducing the essential genes
expression involved in cell proliferation or survival. However, it does
not mean that miRNAs play direct roles in cancers and their
tumorigenesis progress. Although, it has not been elucidated
completely that the changed expression of miRNAs is the pathological
consequence of cancer or cancer is the direct factor of such expression
changes (Nygren et al., 2014).
It is to be noticed that genetic factors can influence miRNA
through extra methylation or disabling histone changes. On the other
hand, miRNA can be proposed as a genetic regulator of the
mentioned factors. Some of miRNAs types act as tumor suppressor
or oncogene which are called “oncomir”. Oncomirs are present in
various tissues of malignancy and are often found in genome areas
with deletion, supplication, or mutation (Chou et al., 2013). Some
miRNAs induce oncogene phenotype by reducing the tumors
suppressor genes expression or regulator genes of cellular differ-
entiation and the programmed death. Some others reduce cancerous
progress through targeting at proto‐oncogenic miRNAs and silencing
them (Rostas et al., 2014).
10974652, 2019, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jcp.28607 by Universitat De Valencia, Wiley Online Library on [30/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
| 19291
5 | m i R N A‐29 IN CANCER TREATME NT
miR‐29 family expression is reduced in most cancers that can be a
sign of its roles in inhibiting the cancerous cells. Studies on cancerous
cells have shown that miR‐29 reduction is mainly caused by the
hypermethylation of CpG areas of miR‐29 promoter. In addition, it
was indicated that miR‐29 can suppress DNMT expression. In
contrary, DNMTs reduces miR‐29 expression through increasing
miR‐29 promoter methylation (Cui et al., 2015; Li et al., 2012).
Antitumor mechanisms of miR‐29 include inhibiting Wnt/β‐catenin
signaling pathway (Tan et al., 2013), induction of tumor suppressor
genes demethylation such as FHIT and WWOX (Fabbri et al., 2007),
reducing LOXL2 expression (Mizuno et al., 2016), inhibition of MUC1
(Tréhoux et al., 2015), downregulation of BC11B (He et al., 2018),
and B7‐H3. Therefore, it seems that increased miR‐29 expression in a
cancerous cell can suppress them.
The experimental studies have shown that chemical prevention
by the herbal compounds from the nutritional sources, due to their
nontoxicity, they may increase the expression of the miR‐29 family in
human cancer cells. For example, curcumin and epigallocatechin
gallate reduce methylation in tumor suppressor genes and increase
the transcription of these genes by involving the active site of DNMT
enzyme. Thus, they control the cancerous cells (Yiannakopoulou,
2015). Razoutol can cause hypomethylation of promotor in triple
negative breast cancer. Furthermore, razoutol can lead to hypo and
hypermethylation of key genes in cancer suppression and oncogenes,
respectively (Medina‐Aguilar et al., 2016). Vitamin C can reduce
methylation in leukemic cells. Moreover, it is shown that taking
vitamin C in patients who take DNA hypomethylation drugs can
improve the efficiency of the drug (Cimmino et al., 2018). Studies
have shown that activating miR‐29 through natural factors is a
promising approach to eradicate human malignancies.
6 | CO NCL USION
miRNAs were discovered in 1993 and have turned to an interesting
research field in the past decade. There is no doubt now about the
importance of miRNAs in the beginning and progress of various
malignancies. By considering this fact that most common methods of
cancer screening cannot diagnose the disease in its initial stages,
detection of the tumorous miRNAs, which are developed gradually in
blood, is a key method for timely diagnosis of cancers. In spite of
many studies in this field, many questions have remained without
answers about the relationship between the involved factors in
miRNAs synthesis, the precise perception of their function in the
disease condition, and the efficient delivery method to tissue.
Whether an optimal treatment with miRNA can be replaced by all
existing treatments or not needs more clinical studies to be answered
(Almeida et al., 2011; Iguchi et al., 2010). Improper expression of
miR‐29 family has been detected in the development and progress of
many malignancies. Thus, miR‐29 family can be used as the clinical
marker in the diagnosis and prognosis of many cancers. Furthermore,

19292 | ALIZADEH
miR‐29 can be a potential target to treat cancer. Since miR‐29 family
expression is reduced in most cancers because of hypermethylation
of genes promoter and this reduced expression starts cancer or make
the cancer invasive, the view of this study is that miR‐29 family
expression can be regulated using the natural factors such as
curcumin, polyphenols, methylation. As well, tumor invasion and
proliferation can be suppressed through this way. Undoubtedly, the
complementary studies can be helpful to determine the molecular
mechanisms of antitumor activity of miR‐29 family and more
extensive studies about the natural factors, which can be useful to
obtain better results in treating the cancerous patients.
CO NFLICT OF I NTERE STS
The authors declare that there are no conflict of interests.
A UT HO R C ONT RI BU TIO N
M. A. and B. B. devised the main conceptual ideas. M. A., A. S., and B.
B. wrote the initial draft of the manuscript. M. A., K. H., and A. B.
prepared figures. F. B., F. A., K. H., and A. B. reviewed and edited the
manuscript. B. B. supervised the study.
OR CID
Behzad Baradaran http://orcid.org/0000-0002-8642-6795
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How to cite this article: Alizadeh M, Safarzadeh A,
Beyranvand F, et al. The potential role of miR‐29 in health and
cancer diagnosis, prognosis, and therapy. J Cell Physiol. 2019;
234:19280–19297. https://doi.org/10.1002/jcp.28607