role of wnt/β-catenin signaling regulatory micrornas in...
TRANSCRIPT
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
1
MINI-REVIEW
Role of Wnt/β-catenin signaling regulatory microRNAs in the pathogenesis of
colorectal cancer †
Farzad Rahmani1, Amir Avan2,3 , Seyed Isaac Hashemy4#, Seyed Mahdi Hassanian1,5,6#
1) Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical
Sciences, Mashhad, Iran.
2) Molecular Medicine Group, Department of Modern Sciences and Technologies, School of
Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
3) Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences,
Mashhad, Iran.
4) Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
5) Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical
Sciences, Mashhad, Iran.
6) Microanatomy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Running title: Wnt/β-catenin signaling regulatory microRNAs in CRC
The authors have no financial conflicts of interest.
Contract grant sponsor: Mashhad University of Medical Sciences (MUMS)
†This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: [10.1002/jcp.25897]
Received 10 January 2017; Revised 6 March 2017; Accepted 6 March 2017 Journal of Cellular Physiology
This article is protected by copyright. All rights reserved DOI 10.1002/jcp.25897
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
2
# Corresponding Authors:
Seyed Mahdi Hassanian, Ph.D.
Department of Medical Biochemistry
School of Medicine, Mashhad University of Medical Sciences
Mashhad, Iran.
Phone: (+98) 5138002375, Fax: (+98) 5138002389
E-mail: [email protected]
Seyed Isaac Hashemy, M.D., Ph.D.
Surgical Oncology Research Center,
Mashhad University of Medical Sciences,
Mashhad, Iran.
Phone: (+98) 5138002366, Fax: (+98) 5138002389
E-mail: [email protected]
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
3
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. In more than 90% of all CRC patients, the master oncogenic Ras-Wnt signaling axis is over-activated. MicroRNAs (miRNAs) are potential novel diagnostic and prognostic biomarkers as well as therapeutic targets for several cancers including lung, breast, gastric and colorectal cancers. Oncogenic or tumor suppressor miRNAs modulate tumor cells proliferation, cell cycle progression, angiogenesis, invasion and metastasis through regulating oncogenic pathways including Wnt/β-catenin signaling. This review summarizes the current knowledge about the role of Wnt/β-catenin signaling regulatory miRNAs in the pathogenesis of colorectal cancer for a better understanding and hence a better management of this disease. This article is protected by
copyright. All rights reserved
Keywords: Wnt/β-catenin signaling, MicroRNA, Colorectal cancer
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
4
Introduction
Colorectal cancer (CRC) is one of the most common malignancies in the world
(Rodrigues et al., 2016). The progression of the CRC from normal colonic epithelial cells to the
malignant phenotype is accompanied by the accumulation of mutations in oncogenes and
tumor-suppressor genes including adenomatous polyposis coli (APC) (Pandurangan, 2013;
Rodrigues et al., 2016; Zhang et al., 2013). The APC is a multi-functional tumor suppressor
protein with inhibitory functions on Wnt/β-catenin signaling pathway (Guo et al., 2016a). APC
mutations induce over-activation of Wnt/β-catenin signaling and over-expression of Wnt
downstream effectors including c-myc, cyclin D1, E-cadherin and etc. leading to cell
proliferation, migration, invasion and metastasis of CRC cells (Stanczak et al., 2011). Mutations
in APC have been found in almost 90% of CRC as well as in all familial adenomatous polyposis
patients (Coppede et al., 2014).
MicroRNAs (miRNAs) are novel promising biomarker candidates for CRC that regulate
various oncogenic pathways, including Wnt/β-catenin signaling (Zhang et al., 2013). MiRNA-
induced Wnt signaling regulation modulates tumorigenesis in brain (Saydam et al., 2009),
colorectal (Kim et al., 2013a; Kim et al., 2011), breast (Cai et al., 2013a; Cai et al., 2013b) and
liver cancers (Wang et al., 2012). In this review role of Wnt/β-catenin signaling regulatory
miRNAs in the pathogenesis of CRC is summarized.
Wnt signaling pathway
Wnt signaling is classified into canonical (β-catenin-dependent) and non-canonical (β-
catenin-independent) pathways (Fortress and Frick, 2015; Niehrs and Acebron, 2012). The
canonical Wnt/β-catenin pathway plays essential roles in different stages of tumor development
including cancer cell proliferation, migration, invasion, tumorigenesis and metastasis (Chua et
al., 2014; Jiang et al., 2016; Song et al., 2015). In the absence of a Wnt ligand, cytoplasmic β-
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
5
catenin protein is phosphorylated at Ser33, Ser37, Thr41 (Yost et al., 1996) and Ser45 (Liu et
al., 2002) by glycogen synthase kinase 3β (GSK3β) and casein kinase 1 (CK1) respectively,
leading to ubiquitination and subsequent degradation of the protein by the proteasomal system
(Huang et al., 2010; Song et al., 2015; Wheelock et al., 2001).
However, in the presence of a Wnt ligand, the receptor/co-receptor complex
phosphorylates and activates the scaffolding protein Disheveled (Dsh) leading to the inhibition
of the GSK-3β. Following deactivation of GSK-3β, β-catenin is not targeted for degradation by
the ubiquitin/proteasome system and as a consequence, the β-catenin accumulates in the
cytoplasm and travel to the nucleus to form complexes with co-regulators of transcription factors
including T cell factor/lymphocyte enhancer factor (TCF/LEF). This complex regulates
transcription of multiple downstream factor genes involved in cellular proliferation,
differentiation, survival and apoptosis (Anastas and Moon, 2013; Clevers, 2006; Clevers and
Nusse, 2012; Kim et al., 2013b; Moon et al., 2004).
Non-canonical Wnt signal transduction is independent of β-catenin stabilization and is
classified into the Wnt/Ca2+ and planar cell polarity (PCP) pathways (Kühl et al., 2000; Pandur et
al., 2002). Wnt/Ca2+ pathway activates transcription factor nuclear factor associated with T cells
(NFAT) to regulate cytoskeletal rearrangements, cell adhesion, migration, and tissue separation
(Kohn and Moon, 2005). In the PCP pathway, the activated Dvl triggers Rho (Habas et al.,
2001; Tanegashima et al., 2008) and Rac branch of signaling (Marlow et al., 2002) which
regulate myosin activation (Weiser et al., 2007) and actin polymerization in stimulated cells
(Gordon and Nusse, 2006). These complicated signaling are integrated for cytoskeletal
changes, cell polarization and motility during gastrulation (Gordon and Nusse, 2006; Seifert and
Mlodzik, 2007).
Aberrant Wnt/β-catenin signaling has been linked to the pathogenesis of various
diseases, including cancer. Over-expression of Wnt or gene mutations in β-catenin, GSK3β,
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
6
Axin or APC leads to over-activation of Wnt/β-catenin pathway. Wnt/β-catenin pathway
regulates E-cadherin via promoting the expression of repressors of this adhesion molecule
including transcriptional factors SNAI1 and SNAI2, and zinc finger E-box binding homeobox 1
(ZEB1) leading to metastasis and invasiveness (Schmalhofer et al., 2009; Yost et al., 1996).
MicroRNAs regulate Wnt/β-catenin signaling pathway
MiRNAs are short non-coding 18-25 nucleotide RNAs (Zhong et al., 2012). MiRNAs are
transcribed by polymerase II as large RNA precursors of variable length (1 kb-3kb), called pri-
miRNA. These precursor molecules are processed within the nucleus by RNase III enzyme
Drosha into pre-miRNA with 60–70 nucleotide stem loop structures. Pre-miRNAs are
transported to the cytoplasm through nuclear pore complexes by a shuttle protein, exportin 5.
Once in the cytoplasm, the Pre-miRNAs are processed by Dicer, a RNase III enzyme, to
generate the single stranded mature miRNA (Fabian and Sonenberg, 2012). Mature miRNAs
assemble into the RNA-induced silencing complex (RISC), which following binding to the
complementary sequence of the target mRNA induces cleavage of the mRNA (Bonfrate et al.,
2013; He and Hannon, 2004).
MiRNAs could regulate the expression of about 30% of the human genome (Schee et
al., 2010) including oncogenes or tumor suppressors (Hosseini et al., 2016). MiRNAs are
involved in almost every type of cancers including lung, breast, gastric carcinoma and colorectal
cancer (Kayani et al., 2011; Kong et al., 2012). Given their tendency to regulate numerous
cellular processes, it is no surprising that aberrant expression of miRNAs be associated with
dysregulation of oncogenic signaling pathways such as Wnt/ β-catenin in cancers (Kong et al.,
2014). Here we discuss about the role of Wnt/β-catenin signaling regulatory miRNAs in the CRC
pathogenesis (Fig. 1).
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
7
Role of Wnt/β-catenin signaling regulatory oncogenic miRNAs in CRC pathology
APC is a key component of the Wnt/β-catenin pathway which together with other
components of the destruction complex suppresses the Wnt/β-catenin signaling through
targeting β-catenin for ubiquitination and degradation (Coppede et al., 2014). Mutation in APC is
associated with the up-regulation of several miRNAs in CRC patients (Diosdado et al., 2009;
Grillari et al., 2010; Lanza et al., 2007; Mogilyansky and Rigoutsos, 2013; Zhou et al., 2014).
For instance, β-catenin binds and activates the promoter of miR-17-92, oncogenic polycistronic
miRNA cluster, but APC suppresses expression of these miRNAs via inducing degradation of β-
catenin. Similarly, up-regulation of β-catenin is positively associated with miR-19a expression in
CRC patients (Li et al., 2016b). Consistently, enforced expression of miR-19a attenuates
inhibitory effects of APC on cellular migration, invasion and growth by targeting tumor
suppressor PTEN (Li et al., 2016b). Consistent with these findings, it has been shown that
expression of miR135b, a key downstream effector of oncogenic pathways, is negatively
correlated with the APC gene expression. Further studies showed that APC is a target gene of
miR135a/b in human CRC cells. Over-expression of miR135b is associated with advanced
tumor grade and poor clinical outcomes (Nagel et al., 2008; Valeri et al., 2014).
Furthermore, oncogenic miR-574-5p activates Wnt/β-catenin signaling through down-
regulation of Quaking 6/7 (Qki6/7) protein (Ji et al., 2013). Qki 6/7 is a RNA binding protein
regulating several cellular processes including cell cycle progression, differentiation and
angiogenesis (Lobbardi et al., 2011; van Mil et al., 2012). Consistently, inhibition of miR-574-5p
suppresses growth of CRC cells in the nude mice (Ji et al., 2013). To further support the
stimulatory effects of oncogenic miRNAs on Wnt/β-catenin pathway, Yu Y et al. showed that
oncogenic miR-21 significantly activates Wnt/β-catenin pathway, through down-regulation of
transforming growth factor beta receptor 2 (TGFβR2), a negative regulator of the Wnt/β-catenin
pathway, in colon cancer cells (Yu et al., 2012). Ectopic expression of miRNA-21 stimulates β-
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
8
catenin-induced TCF/LEF activity leading to up-regulation of c-Myc and cyclin D in colon cancer
cells (Yu et al., 2013). Consistent with these findings, Farooqi et al. demonstrated that
oncogenic miR-155 up-regulates expression of oncogenes including c-Myc, cyclin D1, TCF-1
and LEF-1 through suppressing tumor suppressor HMG-box transcription factor 1 (HBP1)
(Farooqi et al., 2014; YC Wan, 2016). Similarly, miR-15b induces proliferation and metastasis
through up-regulating β-catenin and suppressing Axin2, a component of the destruction
complex, in colon cancer cells. MiR-15b is elevated in CRC individuals which is associated with
poor patient prognosis (Guo et al., 2016a). Moreover, Guo et al. demonstrated that miR-150 is
the most up-regulated microRNA in response to over-activation of Wnt/β-catenin pathway in
human colon cancer cells, HCT116 (Guo et al., 2016b). Interestingly, they showed that
TCF/LEF1 transcription factors bind to the promoter of miR-150 leading to trans-activation of the
miRNA in Wnt/β-catenin deregulated colon cancer cells. Ectopic expression of miR-150 potently
increases cancerous properties including migration and invasion activities and enhances
epithelial-mesenchymal transition (EMT) by targeting CAMP responsive element binding protein
1, CREB1, and EP300, a histone acetyl transferase, in colon cancer cells (Guo et al., 2016b).
To further support the role of stimulatory Wnt/β-catenin oncogenic miRNAs in CRC
pathogenesis Li et al. showed that miR-224 is an oncogenic miRNA that directly targets Wnt/β-
catenin signaling suppressors including GSK3β and secreted Frizzled Related Protein-2 (sFRP-
2), resulting in cytoplasmic accumulation and nuclear translocation of β-catenin thereby up-
regulating the pathway target genes c-Myc and cyclinD1 (Li et al., 2016a). Similarly, miR-29a
activates Wnt/β-catenin signaling via inhibiting Wnt/β-catenin antagonists including Dickkopf
Wnt/β-catenin signaling pathway inhibitor 1 (Dkk1) and sFRP-2 proteins. In contrast to miR-29a,
miR-29b down-regulates Wnt/β-catenin pathway and inhibits cell growth, tumor angiogenesis
and EMT in human colorectal cancer cells. The inhibitory effects of miR-29b on Wnt/β-catenin
pathway is mediated through targeting β-catenin transcription cofactor, B-cell CLL/lymphoma 9-
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
9
like (BCL9L), and transcription factors including transcription factor 7-like 2 (TCF7L2) and SNAI1
in colon cancer cells (Jiang et al., 2016; Kapinas et al., 2010; Subramanian et al., 2014).
Wnt/β-catenin signaling regulatory tumor suppressor miRNAs in CRC pathology
In contrast to oncogenic miRNAs, tumor suppressor counterparts inhibit Wnt/ β-catenin
pathway in CRC patients. Tumor suppressor miR-23b decreases CRC progression through
down-regulation of frizzled 7 (Fzd-7), a Wnt/β-catenin signaling receptor, in CRC individuals
(Zhang et al., 2011). Similarly, miR-7 targets the oncogenic transcription factor Ying Yang 1
(YY1) (Zhang et al., 2013). YY1 protein activates Wnt/β-catenin signaling pathway, thereby
promoting cell proliferation (Zhang et al., 2013). Moreover, miR-34a is another tumor
suppressor miRNA with an inhibitory effect on Wnt/β-catenin signaling pathway (Kim et al.,
2011). It has been shown that loss of miR-34 contributes to neoplastic progression in colorectal
cancer cells and the epigenetic silencing of this miRNA through CpG methylation contributes to
the formation of distant metastases in primary tumors (Siemens et al., 2013). In support of the
regulatory role of tumor suppressor miRNAs on Wnt/β-catenin signaling, Zhang et al. showed
that compared to colon cancer cells, levels of miR-26b is significantly higher in normal colon
cells (Zhang et al., 2014). Further studies showed that miR-26b down-regulates LEF-1
expression by inhibiting Wnt/β-catenin signaling pathway in colon cancer cells (Zhang et al.,
2010).
Furthermore, miR-93 level is decreased in CRC tissues and colorectal carcinoma cell
lines compared with normal colon mucosa (Xiao et al., 2013). Expression of miR-93 potently
decreases expression of Wnt/β-catenin components and effectors. Further studies showed that
miR-93-induced Wnt/β-catenin inhibition is partially mediated through targeting of smad-7, a
protein essential for nuclear accumulation of β-catenin (Tang et al., 2015). Consistently, miR-
101 is another inhibitory Wnt/β-catenin miRNA that its expression is impaired in CRC specimens
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
10
(Strillacci et al., 2009). Enforced expression of this miRNA decreases CRC pro-malignant
features including cell growth, hypoxic survival and invasion, suggesting that MiR-101 functions
as a potent tumor suppressor in CRC patients (Strillacci et al., 2013). Moreover, tumor
suppressor miR-145 expression is significantly decreases in colon cancer cells (Akao et al.,
2006). Recent studies showed that this miRNA inhibits Wnt/β-catenin pathway by disturbing the
intracellular translocation of β-catenin into the nucleus (Yamada et al., 2013). Further studies
showed that miR-145 targets catenin δ-1, a regulator of cytoskeletal reorganization that binds to
p21-activated kinase 4 (PAK4). The latter one is a modulator of intracellular translocation of β-
catenin to the nucleolus which is a key step for the signaling pathway activation. Similarly, miR-
185 and miR-320a expressions are significantly down-regulated in colon cancer cells compared
with normal colon cells (Dong-Xu et al., 2015; Schepeler et al., 2008). This miRNAs suppress
cell proliferation in colon cancer cells through inhibition of Wnt/β-catenin pathway and down-
regulation of signaling effector genes including c-Myc and cyclin D1 (Dong-Xu et al., 2015; Sun
et al., 2012; Zhang et al., 2015). These studies clearly demonstrate that miRNAs can modulate
the pathogenesis of CRC through regulating Wnt/β-catenin signaling pathway and should be
pursued as potential novel diagnostic, prognostic biomarkers as well as a therapeutic target for
development of novel drugs for CRC patients.
Conclusion
This review summarizes the recent findings on the Role of Wnt/β-catenin signaling
regulatory miRNAs in the pathogenesis of colorectal cancer (Table 1). Through regulating
Wnt/β-catenin signaling pathway, oncogenic or tumor suppressor miRNAs modulate colon
cancer cells proliferation, invasion and metastasis (Fig. 2). Study results clearly support the
hypothesis that these regulatory miRNAs could be novel diagnostic factor as well as a clinically
invaluable post-treatment marker for CRC patients.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
11
From this point of view, pharmacological inhibition or restoration of miRNAs might
attenuate the aggressive behavior of CRC that either alone or in combination with standard
clinically chemotherapy agents can be used in patients with advanced CRC cancer. Noting that
a role for miRNAs in regulation of Wnt/β-catenin pathway has been reported, several studies
investigated the interplay between Wnt/β-catenin signaling and miRNA expression by
determining if inhibition of one pathway by specific inhibitors is mirrored in the other. Results
demonstrated that not only Wnt/β-catenin signaling components including APC, β-catenin and
Axin are targets for miRNAs but also many miRNAs promoters are
downstream effectors of Wnt/β-catenin pathway. These findings support the hypothesis that
modulation of miRNA profile is a key mechanism in anti-tumor properties of Wnt/β-catenin
pharmacological inhibitors in cellular or clinical models. Understanding of the effect of specific
Wnt/β-catenin pharmacological inhibitors on miRNA profile could therefore help to design of
agent with more specificity and less side effects than those currently in use.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
12
References:
Akao Y, Nakagawa Y, Naoe T. 2006. MicroRNAs 143 and 145 are possible common onco-
microRNAs in human cancers. Oncology reports 16(4):845-850.
Anastas JN, Moon RT. 2013. WNT signalling pathways as therapeutic targets in cancer. Nature
reviews Cancer 13(1):11-26.
Bonfrate L, Altomare DF, Di Lena M, Travaglio E, Rotelli MT, De Luca A, Portincasa P. 2013.
MicroRNA in colorectal cancer: new perspectives for diagnosis, prognosis and
treatment. J Gastrointestin Liver Dis 22(3):311-320.
Cai J, Guan H, Fang L, Yang Y, Zhu X, Yuan J, Wu J, Li M. 2013a. MicroRNA-374a activates
Wnt/beta-catenin signaling to promote breast cancer metastasis. The Journal of clinical
investigation 123(2):566-579.
Cai W-Y, Wei T-Z, Luo Q-C, Wu Q-W, Liu Q-F, Yang M, Ye G-D, Wu J-F, Chen Y-Y, Sun G-B.
2013b. The Wnt–β-catenin pathway represses let-7 microRNA expression through
transactivation of Lin28 to augment breast cancer stem cell expansion. J Cell Sci
126(13):2877-2889.
Chua M-S, Ma L, Wei W, So S. 2014. WNT/β-catenin pathway activation in hepatocellular
carcinoma: a clinical perspective. Gastrointestinal Cancer: Targets and Therapy:49.
Clevers H. 2006. Wnt/beta-catenin signaling in development and disease. Cell 127(3):469-480.
Clevers H, Nusse R. 2012. Wnt/β-catenin signaling and disease. Cell 149(6):1192-1205.
Coppede F, Lopomo A, Spisni R, Migliore L. 2014. Genetic and epigenetic biomarkers for
diagnosis, prognosis and treatment of colorectal cancer. World journal of
gastroenterology 20(4):943-956.
Diosdado B, van de Wiel MA, Terhaar Sive Droste JS, Mongera S, Postma C, Meijerink WJ,
Carvalho B, Meijer GA. 2009. MiR-17-92 cluster is associated with 13q gain and c-myc
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
13
expression during colorectal adenoma to adenocarcinoma progression. Br J Cancer
101(4):707-714.
Dong-Xu W, Jia L, Su-Juan Z. 2015. MicroRNA-185 is a novel tumor suppressor by negatively
modulating the Wnt/beta-catenin pathway in human colorectal cancer. Indian journal of
cancer 52 Suppl 3:E182-185.
Fabian MR, Sonenberg N. 2012. The mechanics of miRNA-mediated gene silencing: a look
under the hood of miRISC. Nature structural & molecular biology 19(6):586-593.
Farooqi AA, Qureshi MZ, Coskunpinar E, Naqvi SK-U-H, Yaylim I, Ismail M. 2014. miR-421,
miR-155 and miR-650: Emerging Trends of Regulation of Cancer and Apoptosis. Asian
Pacific Journal of Cancer Prevention 15(5):1909-1912.
Fortress AM, Frick KM. 2015. Hippocampal Wnt Signaling Memory Regulation and Hormone
Interactions. The Neuroscientist:1073858415574728.
Gordon MD, Nusse R. 2006. Wnt signaling: multiple pathways, multiple receptors, and multiple
transcription factors. Journal of Biological Chemistry 281(32):22429-22433.
Grillari J, Hackl M, Grillari-Voglauer R. 2010. miR-17-92 cluster: ups and downs in cancer and
aging. Biogerontology 11(4):501-506.
Guo X, Zhang Y, Li J, Liao M. 2016a. miR-15b facilitates the progression of colorectal cancer
via targeting β-catenin and Axin2. Int J Clin Exp Pathol 9(9):8990-8996.
Guo YH, Wang LQ, Li B, Xu H, Yang JH, Zheng LS, Yu P, Zhou AD, Zhang Y, Xie SJ, Liang
ZR, Zhang CM, Zhou H, Qu LH. 2016b. Wnt/beta-catenin pathway transactivates
microRNA-150 that promotes EMT of colorectal cancer cells by suppressing CREB
signaling. Oncotarget 7(27):42513-42526.
Habas R, Kato Y, He X. 2001. Wnt/Frizzled activation of Rho regulates vertebrate gastrulation
and requires a novel Formin homology protein Daam1. Cell 107(7):843-854.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
14
He L, Hannon GJ. 2004. MicroRNAs: small RNAs with a big role in gene regulation. Nature
reviews Genetics 5(7):522-531.
Hosseini M, Khatamianfar S, Hassanian S, Nedaeinia R, Shafiee M, Maftouh M, Ghayour-
Mobarhan M, Sales S, Avan A. 2016. Exosome-encapsulated microRNAs as potential
circulating biomarkers in colon cancer. Current pharmaceutical design.
Huang K, Zhang JX, Han L, You YP, Jiang T, Pu PY, Kang CS. 2010. MicroRNA roles in beta-
catenin pathway. Molecular cancer 9:252.
Ji S, Ye G, Zhang J, Wang L, Wang T, Wang Z, Zhang T, Wang G, Guo Z, Luo Y, Cai J, Yang
JY. 2013. miR-574-5p negatively regulates Qki6/7 to impact beta-catenin/Wnt signalling
and the development of colorectal cancer. Gut 62(5):716-726.
Jiang Q, He M, Guan S, Ma M, Wu H, Yu Z, Jiang L, Wang Y, Zong X, Jin F, Wei M. 2016.
MicroRNA-100 suppresses the migration and invasion of breast cancer cells by targeting
FZD-8 and inhibiting Wnt/beta-catenin signaling pathway. Tumour biology : the journal of
the International Society for Oncodevelopmental Biology and Medicine 37(4):5001-5011.
Kapinas K, Kessler C, Ricks T, Gronowicz G, Delany AM. 2010. miR-29 modulates Wnt
signaling in human osteoblasts through a positive feedback loop. The Journal of
biological chemistry 285(33):25221-25231.
Kayani M, Kayani MA, Malik FA, Faryal R. 2011. Role of miRNAs in breast cancer. Asian Pacific
journal of cancer prevention : APJCP 12(12):3175-3180.
Kim NH, Cha YH, Kang SE, Lee Y, Lee I, Cha SY, Ryu JK, Na JM, Park C, Yoon HG, Park GJ,
Yook JI, Kim HS. 2013a. p53 regulates nuclear GSK-3 levels through miR-34-mediated
Axin2 suppression in colorectal cancer cells. Cell cycle 12(10):1578-1587.
Kim NH, Kim HS, Kim N-G, Lee I, Choi H-S, Li X-Y, Kang SE, Cha SY, Ryu JK, Na JM. 2011.
p53 and miRNA-34 are suppressors of canonical Wnt signaling. Science signaling
4(197):ra71.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
15
Kim W, Kim M, Jho E-h. 2013b. Wnt/β-catenin signalling: from plasma membrane to nucleus.
Biochemical Journal 450(1):9-21.
Kohn AD, Moon RT. 2005. Wnt and calcium signaling: β-catenin-independent pathways. Cell
calcium 38(3):439-446.
Kong W, He L, Richards EJ, Challa S, Xu CX, Permuth-Wey J, Lancaster JM, Coppola D,
Sellers TA, Djeu JY, Cheng JQ. 2014. Upregulation of miRNA-155 promotes tumour
angiogenesis by targeting VHL and is associated with poor prognosis and triple-negative
breast cancer. Oncogene 33(6):679-689.
Kong YW, Ferland-McCollough D, Jackson TJ, Bushell M. 2012. microRNAs in cancer
management. The Lancet Oncology 13(6):e249-258.
Kühl M, Sheldahl LC, Park M, Miller JR, Moon RT. 2000. The Wnt/Ca 2+ pathway: a new
vertebrate Wnt signaling pathway takes shape. Trends in genetics 16(7):279-283.
Lanza G, Ferracin M, Gafa R, Veronese A, Spizzo R, Pichiorri F, Liu CG, Calin GA, Croce CM,
Negrini M. 2007. mRNA/microRNA gene expression profile in microsatellite unstable
colorectal cancer. Molecular cancer 6:54.
Li T, Lai Q, Wang S, Cai J, Xiao Z, Deng D, He L, Jiao H, Ye Y, Liang L, Ding Y, Liao W. 2016a.
MicroRNA-224 sustains Wnt/beta-catenin signaling and promotes aggressive phenotype
of colorectal cancer. Journal of experimental & clinical cancer research : CR 35:21.
Li Y, Lauriola M, Kim D, Francesconi M, D'Uva G, Shibata D, Malafa MP, Yeatman TJ, Coppola
D, Solmi R, Cheng JQ. 2016b. Adenomatous polyposis coli (APC) regulates miR17-92
cluster through beta-catenin pathway in colorectal cancer. Oncogene 35(35):4558-4568.
Liu C, Li Y, Semenov M, Han C, Baeg G-H, Tan Y, Zhang Z, Lin X, He X. 2002. Control of β-
catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108(6):837-847.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
16
Lobbardi R, Lambert G, Zhao J, Geisler R, Kim HR, Rosa FM. 2011. Fine-tuning of Hh signaling
by the RNA-binding protein Quaking to control muscle development. Development
(Cambridge, England) 138(9):1783-1794.
Marlow F, Topczewski J, Sepich D, Solnica-Krezel L. 2002. Zebrafish Rho kinase 2 acts
downstream of Wnt11 to mediate cell polarity and effective convergence and extension
movements. Current biology 12(11):876-884.
Mogilyansky E, Rigoutsos I. 2013. The miR-17/92 cluster: a comprehensive update on its
genomics, genetics, functions and increasingly important and numerous roles in health
and disease. Cell Death Differ 20(12):1603-1614.
Moon RT, Kohn AD, De Ferrari GV, Kaykas A. 2004. WNT and β-catenin signalling: diseases
and therapies. Nature Reviews Genetics 5(9):691-701.
Nagel R, le Sage C, Diosdado B, van der Waal M, Oude Vrielink JA, Bolijn A, Meijer GA, Agami
R. 2008. Regulation of the adenomatous polyposis coli gene by the miR-135 family in
colorectal cancer. Cancer research 68(14):5795-5802.
Niehrs C, Acebron SP. 2012. Mitotic and mitogenic Wnt signalling. The EMBO journal
31(12):2705-2713.
Pandur P, Maurus D, Kühl M. 2002. Increasingly complex: new players enter the Wnt signaling
network. Bioessays 24(10):881-884.
Pandurangan AK. 2013. Potential Targets for Prevention of Colorectal Cancer: a Focus on
PI3K/Akt/mTOR and Wnt Pathways. Asian Pacific Journal of Cancer Prevention
14(4):2201-2205.
Rodrigues D, Longatto-Filho A, Martins SF. 2016. Predictive Biomarkers in Colorectal Cancer:
From the Single Therapeutic Target to a Plethora of Options. BioMed research
international 2016:6896024.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
17
Saydam O, Shen Y, Würdinger T, Senol O, Boke E, James MF, Tannous BA, Stemmer-
Rachamimov AO, Yi M, Stephens RM. 2009. Downregulated microRNA-200a in
meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/β-
catenin signaling pathway. Molecular and cellular biology 29(21):5923-5940.
Schee K, Fodstad O, Flatmark K. 2010. MicroRNAs as biomarkers in colorectal cancer. The
American journal of pathology 177(4):1592-1599.
Schepeler T, Reinert JT, Ostenfeld MS, Christensen LL, Silahtaroglu AN, Dyrskjot L, Wiuf C,
Sorensen FJ, Kruhoffer M, Laurberg S, Kauppinen S, Orntoft TF, Andersen CL. 2008.
Diagnostic and prognostic microRNAs in stage II colon cancer. Cancer research
68(15):6416-6424.
Schmalhofer O, Brabletz S, Brabletz T. 2009. E-cadherin, beta-catenin, and ZEB1 in malignant
progression of cancer. Cancer Metastasis Rev 28(1-2):151-166.
Seifert JR, Mlodzik M. 2007. Frizzled/PCP signalling: a conserved mechanism regulating cell
polarity and directed motility. Nature Reviews Genetics 8(2):126-138.
Siemens H, Neumann J, Jackstadt R, Mansmann U, Horst D, Kirchner T, Hermeking H. 2013.
Detection of miR-34a promoter methylation in combination with elevated expression of c-
Met and beta-catenin predicts distant metastasis of colon cancer. Clinical cancer
research : an official journal of the American Association for Cancer Research
19(3):710-720.
Song JL, Nigam P, Tektas SS, Selva E. 2015. microRNA regulation of Wnt signaling pathways
in development and disease. Cellular signalling 27(7):1380-1391.
Stanczak A, Stec R, Bodnar L, Olszewski W, Cichowicz M, Kozlowski W, Szczylik C, Pietrucha
T, Wieczorek M, Lamparska-Przybysz M. 2011. Prognostic significance of Wnt-1, β-
catenin and E-cadherin expression in advanced colorectal carcinoma. Pathology &
Oncology Research 17(4):955-963.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
18
Strillacci A, Griffoni C, Sansone P, Paterini P, Piazzi G, Lazzarini G, Spisni E, Pantaleo MA,
Biasco G, Tomasi V. 2009. MiR-101 downregulation is involved in cyclooxygenase-2
overexpression in human colon cancer cells. Experimental cell research 315(8):1439-
1447.
Strillacci A, Valerii MC, Sansone P, Caggiano C, Sgromo A, Vittori L, Fiorentino M, Poggioli G,
Rizzello F, Campieri M, Spisni E. 2013. Loss of miR-101 expression promotes Wnt/beta-
catenin signalling pathway activation and malignancy in colon cancer cells. The Journal
of pathology 229(3):379-389.
Subramanian M, Rao SR, Thacker P, Chatterjee S, Karunagaran D. 2014. MiR-29b
downregulates canonical Wnt signaling by suppressing coactivators of beta-catenin in
human colorectal cancer cells. Journal of cellular biochemistry 115(11):1974-1984.
Sun JY, Huang Y, Li JP, Zhang X, Wang L, Meng YL, Yan B, Bian YQ, Zhao J, Wang WZ, Yang
AG, Zhang R. 2012. MicroRNA-320a suppresses human colon cancer cell proliferation
by directly targeting beta-catenin. Biochemical and biophysical research communications
420(4):787-792.
Tanegashima K, Zhao H, Dawid IB. 2008. WGEF activates Rho in the Wnt–PCP pathway and
controls convergent extension in Xenopus gastrulation. The EMBO journal 27(4):606-
617.
Tang Q, Zou Z, Zou C, Zhang Q, Huang R, Guan X, Li Q, Han Z, Wang D, Wei H, Gao X, Wang
X. 2015. MicroRNA-93 suppress colorectal cancer development via Wnt/beta-catenin
pathway downregulating. Tumour biology : the journal of the International Society for
Oncodevelopmental Biology and Medicine 36(3):1701-1710.
Valeri N, Braconi C, Gasparini P, Murgia C, Lampis A, Paulus-Hock V, Hart JR, Ueno L,
Grivennikov SI, Lovat F, Paone A, Cascione L, Sumani KM, Veronese A, Fabbri M,
Carasi S, Alder H, Lanza G, Gafa R, Moyer MP, Ridgway RA, Cordero J, Nuovo GJ,
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
19
Frankel WL, Rugge M, Fassan M, Groden J, Vogt PK, Karin M, Sansom OJ, Croce CM.
2014. MicroRNA-135b promotes cancer progression by acting as a downstream effector
of oncogenic pathways in colon cancer. Cancer cell 25(4):469-483.
van Mil A, Grundmann S, Goumans MJ, Lei Z, Oerlemans MI, Jaksani S, Doevendans PA,
Sluijter JP. 2012. MicroRNA-214 inhibits angiogenesis by targeting Quaking and
reducing angiogenic growth factor release. Cardiovascular research 93(4):655-665.
Wang X, Chen J, Li F, Lin Y, Zhang X, Lv Z, Jiang J. 2012. MiR-214 inhibits cell growth in
hepatocellular carcinoma through suppression of β-catenin. Biochemical and biophysical
research communications 428(4):525-531.
Weiser DC, Pyati UJ, Kimelman D. 2007. Gravin regulates mesodermal cell behavior changes
required for axis elongation during zebrafish gastrulation. Genes & development
21(12):1559-1571.
Wheelock MJ, Soler AP, Knudsen KA. 2001. Cadherin junctions in mammary tumors. Journal of
mammary gland biology and neoplasia 6(3):275-285.
Xiao ZG, Deng ZS, Zhang YD, Zhang Y, Huang ZC. 2013. Clinical significance of microRNA-93
downregulation in human colon cancer. European journal of gastroenterology &
hepatology 25(3):296-301.
Yamada N, Noguchi S, Mori T, Naoe T, Maruo K, Akao Y. 2013. Tumor-suppressive microRNA-
145 targets catenin δ-1 to regulate Wnt/β-catenin signaling in human colon cancer cells.
Cancer letters 335(2):332-342.
YC Wan TL, YD Han, HY Zhang, H Lin, B Zhang. 2016. MicroRNA‑155 enhances the activation
of Wnt/β‑catenin signaling in colorectal carcinoma by suppressing HMG‑box
transcription factor 1. Molecular Medicine Reports 13:2221-2228.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
20
Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT. 1996. The axis-inducing activity,
stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by
glycogen synthase kinase 3. Genes Dev 10(12):1443-1454.
Yu Y, Kanwar SS, Patel BB, Oh P-S, Nautiyal J, Sarkar FH, Majumdar AP. 2012. MicroRNA-21
induces stemness by downregulating transforming growth factor beta receptor 2
(TGFβR2) in colon cancer cells. Carcinogenesis 33(1):68-76.
Yu Y, Sarkar FH, Majumdar APN. 2013. Down-regulation of miR-21 Induces Differentiation of
Chemoresistant Colon Cancer Cells and Enhances Susceptibility to Therapeutic
Regimens. Translational Oncology 6(2):180-186.
Zhang H, Hao Y, Yang J, Zhou Y, Li J, Yin S, Sun C, Ma M, Huang Y, Xi JJ. 2011. Genome-
wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer
metastasis. Nature communications 2:554.
Zhang N, Li X, Wu CW, Dong Y, Cai M, Mok MT, Wang H, Chen J, Ng SS, Chen M, Sung JJ,
Yu J. 2013. microRNA-7 is a novel inhibitor of YY1 contributing to colorectal
tumorigenesis. Oncogene 32(42):5078-5088.
Zhang Y, Lin C, Liao G, Liu S, Ding J, Tang F, Wang Z, Liang X, Li B, Wei Y. 2015. MicroRNA-
506 suppresses tumor proliferation and metastasis in colon cancer by directly targeting
the oncogene EZH2. Oncotarget 6(32):32586.
Zhang Z, Florez S, Gutierrez-Hartmann A, Martin JF, Amendt BA. 2010. MicroRNAs regulate
pituitary development, and microRNA 26b specifically targets lymphoid enhancer factor
1 (Lef-1), which modulates pituitary transcription factor 1 (Pit-1) expression. The Journal
of biological chemistry 285(45):34718-34728.
Zhang Z, Kim K, Li X, Moreno M, Sharp T, Goodheart MJ, Safe S, Dupuy AJ, Amendt BA. 2014.
MicroRNA-26b represses colon cancer cell proliferation by inhibiting lymphoid enhancer
factor 1 expression. Molecular cancer therapeutics 13(7):1942-1951.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
21
Zhong X, Coukos G, Zhang L. 2012. miRNAs in human cancer. Methods in molecular biology
(Clifton, NJ) 822:295-306.
Zhou JJ, Zheng S, Sun LF, Zheng L. 2014. MicroRNA regulation network in colorectal cancer
metastasis. World J Biol Chem 5(3):301-307.
Figure legends
Figure 1. Schematic representation of the role of Wnt/β-catenin signaling regulatory microRNAs
in the pathogenesis of colorectal cancer.
Figure 2. Regulatory functions of oncogenic and tumor suppressor miRNAs on Wnt/β-catenin
signaling pathway in CRC.
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
22
Table 1.
Oncogenic and tumor suppressor miRNAs regulate the pathogenesis of colorectal cancer
through targeting the specific components of the Wnt/β-catenin signaling pathway.
microRNA Target Effect Reference
miR135b miR-15b miR-574-5p miR-21 miR-224 miR-29a miR-19a
mir-150 miR-320a miR-29b miR-23b miR-34a miR-26b miR-93 miR-145 miR-7 mir-155
APC Axin2 β-catenin, Qki6/7, p27 TCF/LEF, TGFβR2 GSK3β, sFRP-2 sFRP-2, DKK1 PTEN
CREB1, EP300 β-catenin TCF7L2,BCL9L,SNAI1 Fzd-7 Wnt 1 LEF-1 smad-7 catenin δ-1, PAK4 YY1 HBP1
Oncogene
Oncogene
Oncogene
Oncogene
Oncogene
Oncogene
Oncogene
Oncogene
Tumor suppressor
Tumor suppressor
Tumor suppressor
Tumor suppressor
Tumor suppressor
Tumor suppressor
Tumor suppressor
Tumor suppressor
Tumor suppressor
(Nagel et al., 2008) (Guo et al., 2016a) (Ji et al., 2013) (Yu et al., 2013) (Li et al., 2016a) (Kapinas et al.,
2010)
(Li et al., 2016b)
(Guo et al., 2016b) (Sun et al., 2012) (Subramanian et al., 2014) (Zhang et al., 2011) (Kim et al., 2011) (Zhang et al., 2010) (Tang et al., 2015) (Yamada et al., 2013) (Zhang et al., 2013) (YC Wan, 2016)
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
23
Figure 1
Acc
epte
d A
rtic
le
This article is protected by copyright. All rights reserved
24
Figure 2
本文献由“学霸图书馆-文献云下载”收集自网络,仅供学习交流使用。
学霸图书馆(www.xuebalib.com)是一个“整合众多图书馆数据库资源,
提供一站式文献检索和下载服务”的24 小时在线不限IP
图书馆。
图书馆致力于便利、促进学习与科研,提供最强文献下载服务。
图书馆导航:
图书馆首页 文献云下载 图书馆入口 外文数据库大全 疑难文献辅助工具