Regulation of Metastasis by microRNAs in Ovarian Cancer

Abstract

Ovarian cancer (OC) is the second most common and the most fatal gynecologic cancer in the United States. Over the last decade, various targeted therapeutics have been introduced but there has been no corresponding improvement in patient survival mainly because of the lack of effective early detection methods. microRNAs (miRs) are small, non-coding RNAs that regulate gene expression post-transcriptionally. Accumulating data suggest central regulatory roles of miRs in modulating OC initiation, progression, and metastasis. More recently, aberrant miR expression has been also associated with cancer stem cell (CSC) phenotypes and development of CSC chemo-resistance. Here, we review recent advances on miRs and OC metastasis and discuss the concept that miRs are involved in both CSC transformation and subsequent OC metastasis. Finally, we describe the prevalence of circulating miRs and assess their potential utilities as biomarkers for OC diagnosis, prognosis, and therapeutics.

Full text

MINI REVIEW ARTICLE
published: 10 June 2014
doi: 10.3389/fonc.2014.00143
Regulation of metastasis by microRNAs in ovarian cancer
Yongchao Wang 1, Sangmi Kim2and Il-man Kim1,3 *
1Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA
2Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA
3Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA
Edited by:
Shailender S. Kanwar, University of
Michigan, USA
Reviewed by:
Santos Mañes, Consejo Superior de
Investigaciones Científicas, Spain
Vinesh KumarThidil Puliyappadamba,
University of Alabama, USA
*Correspondence:
Il-man Kim, Department of
Biochemistry and Molecular Biology,
Vascular Biology Center, Medical
College of Georgia, Georgia Regents
University, CB-3717, 1459 Laney
Walker Blvd, Augusta, GA 30912, USA
e-mail: ilkim@gru.edu
Ovarian cancer (OC) is the second most common and the most fatal gynecologic cancer
in the United States. Over the last decade, various targeted therapeutics have been intro-
duced but there has been no corresponding improvement in patient survival mainly because
of the lack of effective early detection methods. microRNAs (miRs) are small, non-coding
RNAs that regulate gene expression post-transcriptionally. Accumulating data suggest cen-
tral regulatory roles of miRs in modulating OC initiation, progression, and metastasis. More
recently, aberrant miR expression has been also associated with cancer stem cell (CSC)
phenotypes and development of CSC chemo-resistance. Here, we review recent advances
on miRs and OC metastasis and discuss the concept that miRs are involved in both CSC
transformation and subsequent OC metastasis. Finally, we describe the prevalence of cir-
culating miRs and assess their potential utilities as biomarkers for OC diagnosis, prognosis,
and therapeutics.
Keywords: ovarian cancer, miRs, cancer stem cells, epithelial–mesenchymal transition, extracellular matrix,
angiogenesis
INTRODUCTION
Ovarian cancer (OC) is the second most common gynecologic
cancer and the deadliest malignancy among women in the United
States (1). The current standard treatment rests on surgery fol-
lowed by platinum-based chemotherapy. Early disease may be
successfully removed with surgery alone, but most patients with
OC are diagnosed at later stages. Advanced diseases, especially
those metastasized, require complex treatment and management,
accounting for high morbidity and mortality associated with OC.
Cancer antigen 125 (CA-125), the currently available OC diag-
nostic marker, can only be adopted in advanced stages and has
limited utility due to its lack of sensitivity and specificity (2–6).
Therefore, development of novel biomarkers for early detection of
OC is imperative and, toward the goal, research efforts to under-
stand the detailed mechanism underlying its tumorigenesis and
metastasis are warranted.
microRNAs (miRNAs or miRs) are small non-coding RNAs.
They are first transcribed as primary miR transcripts (pri-miRs)
and cropped by the Drosha complex into premature miRs (pre-
miRs). Following the cleavage, exportin-5 mediates the nuclear
translocation of the pre-miRs, which are further processed by the
Dicer complex into mature miRs. The mature miRs are incor-
porated into RNA-induced silencing complex to execute gene-
silencing effect either by repressing the translation or directly
inhibiting messenger RNA (mRNA) stability. Notably, the 30
untranslated regions (UTRs) of each mRNA usually have mul-
tiple miR binding sites and conversely each miR has multiple or
even up to hundreds of target mRNAs as well. Therefore, even the
subtle change of miR expression levels could be amplified in effect
and consequently alters the functionality and phenotype of tar-
geted cells by adjusting their repertoires. The abnormal expression
of miRs in cancer leads to significant pathological consequences.
Oncogenesis is conferred either by overexpression of miRs tar-
geting tumor suppressors or loss of miRs that act as tumor sup-
pressors. Recently, the involvement of miRs in tumorigenesis and
metastasis of OC has been increasingly reported and potential
utility of miRs in early detection of OC has been proposed (7–15).
microRNAs AND OVARIAN CANCER STEM CELLS
A subpopulation of stem-like cells have been isolated and identi-
fied in several distinct malignancies. These stem-like cells, named
cancer stem cells (CSCs), are characterized as possessing the
unlimited self-renewal capacity and pluripotency and thus, they
could differentiate into various cell types and confer the hetero-
geneity of tumor cells (16). It is speculated that CSCs are evolved
from resident stem cells harbored in tissues and are suggested
to be genetically dynamic during tumor progression (17). Alter-
natively, epithelial–mesenchymal transition (EMT) could render
CSC formation as illustrated in Figures 1A,B.
Since Bapat et al. first reported the involvement of CSCs in ovar-
ian tumorigenesis (18), CSCs have been increasingly documented
in OC cell lines, and tumor tissues and serum of patients (7–12).
Using various markers characterizing ovarian CSCs such as CD44,
117, 133, 24, and aldehyde dehydrogenase-1 A1 (ALDH1), several
studies suggest that the central regulatory roles of miRs in OC
tumorigenesis are derived from their involvement in genetic alter-
ation of CSCs that affects the functionality of CSCs, as summarized
in Table 1.
Chen et al. compared the expression levels of miR-200c
between CD117+CD44+ovarian CSCs and CD117−CD44−
CSCs and found that miR-200c was present predominantly
in CD117−CD44−CSCs. Overexpression of miR-200c in
CD117+CD44+CSCs significantly down-regulated the expression
of ZEB-1 and vimentin, leading to an up-regulation of E-cadherin
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Wang et al. miRs in ovarian cancer metastasis
FIGURE 1 | microRNAs regulating tumor metastasis in ovarian cancer.
(A) Normal epithelium and potentially harbored stem cells. (B) miRs that are
implicated in modulation of cancer stem cell (CSC) transformation and
epithelial–mesenchymal transition (EMT) process. (C) miRs that are involved
in tumor angiogenesis. Tumor angiogenesis, which is required for further
tumor growth, is proven to be a handy process that facilitates tumor
metastasis. (D) miR-355 that increases cell–extracellular matrix (ECM)
interaction.
expression and dramatic reduction in the capacity of colony for-
mation, migration, and invasion in vitro. The miR-200c overex-
pression also decreased the magnitude of metastasis in xenograft
models of CD117+CD44+CSCs (7). Similarly, miR-200a was also
down-regulated in ovarian CD133+CSCs than in CD133−CSCs,
and gain-of-function of miR-200a in CD133+cells inhibited the
migration and invasion of CD133+ovarian CSCs. Mechanisti-
cally, ZEB-2 was shown to be the target of miR-200a (8). Xu et al.
examined the role of miR-214 on formation of ovarian CSC phe-
notype, and found that enforced expression of miR-214 targeted
P53/Nanog axis and contributed to ovarian CSC confluence and
the ability of self-renewal (10).
microRNAs may also underlie the mechanism of CSC-induced
development of chemo-resistance. Park et al. showed overexpres-
sion of miR-23b, miR-27a, miR-27b, miR-346, miR-424, and miR-
503 in ALDH1+and chemoresistant OC cells, and among those,
miR-27 expression level was also correlated with metastasis mag-
nitude of OC (9). In human OC cells, miR-199a repressed CD44
expression and inhibited the proliferation, migration, and inva-
sion of CD44+CD117+ovarian CSCs. The inhibition of CD44 by
miR-199a reduced the expression of the multidrug resistance gene
ABCG2, and thereby increased the chemosensitivity of ovarian
CSCs (11). In addition, miR-199a was also implicated in cisplatin
resistance by which its inhibition increased mTOR expression and
decreased cisplatin-induced apoptosis in vitro (12).
microRNAs AND EPITHELIAL–MESENCHYMAL TRANSITION
Epithelial–mesenchymal transition in tumor is a process in which
tumor cells loosen various interactions including cell–cell and cell–
matrix, and are ready to detach, migrate, and metastasize through
blood or lymph vessels (13,21,23). EMT is thought to be a cru-
cial event that leads to tumor metastasis, possibly by increasing
stem-like properties in cancer cells and facilitating their seeding in
distance to form secondary tumors as illustrated in Figures 1A,B.
Accumulating data points to regulatory roles of miRs on EMT
phenotype, which is controlled by canonical pathways such as
WNT and transforming growth factor pathways in OC as shown
in Table 1.
microRNA-125a is widely reported as a tumor suppressor in
various malignancies including OC. Karen et al. showed that
miR-125a can inhibit EMT process in which overexpression of
miR-125a induced the reversal of EMT in highly invasive OC cells
(13). Using multiple biochemical approaches, epidermal growth
factor receptor (EGFR) was proposed as a signaling pathway to
suppress miR-125a expression via ETS family transcription fac-
tor, PEA3 in that study. Moreover, AT-rich interactive domain
3B (ARID3B) was shown to be the target of miR-125a to exert
the EMT repression function (13). Similarly, miR-138 was down-
regulated in highly invasive OC cell lines whereas in vivo overex-
pression of miR-138 inhibited OC metastasis (14). miR-138 has
been shown to directly repress the expression of genes associated
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Wang et al. miRs in ovarian cancer metastasis
Table 1 | microRNAs aberrantly expressed in ovarian cancer and their target genes.
miRNA Targets Effects on tumor metastasis Reference
CSC-RELATED miRs
miR-23b N/I Enhances CSC transformation (9)
miR-27a, b VEGF, Cox2, and Sp1 Enhance CSC transformation and angiogenesis (9,19)
miR-214 P53/Nanog Enhances CSC transformation (10)
miR-346 N/I Enhances CSC transformation (9)
miR-424 N/I Enhances CSC transformation (9)
miR-503 N/I Enhances CSC transformation (9)
miR-199a CD44, mTOR, HIF-1α, VEGF, HER2, and HER3 Inhibits CSC transformation and angiogenesis (11,12,20)
miR-200a ZEB-2 Inhibits CSC transformation and EMT process (8,15)
miR-200c ZEB-1 and vimentin Inhibits CSC transformation and EMT process (7,15)
EMT-RELATED miRs
miR-20a PTEN Enhances EMT process (21)
miR-34 N/I Inhibits EMT process (22,23)
miR-125a AT-rich interactive domain 3B (ARID3B) Inhibits EMT process (13)
miR-138 SRY-related high-mobility group box (SOX4) and HIF-1αInhibits EMT process (14)
miR-141 N/I Inhibits EMT process (15)
miR-200b N/I Inhibits EMT process (15)
miR-429 N/I Inhibits EMT process (15)
ECM-RELATED miR
miR-355 Tenascin C (TNC) Increases cell–ECM interaction (24)
ANGIOGENESIS-RELATED miRs
miR-22 N/I Increases angiogenesis (25)
miR-150, 146a N/I Increase angiogenesis (26)
miR-182 BRCA1 Increases angiogenesis (27)
miR-124 N/I Decreases angiogenesis (28)
miR-125b HIF-1α, VEGF, HER2, and HER3 Decreases angiogenesis (20)
miR-145 p70S6K1, HIF-1α, and VEGF Decreases angiogenesis (29)
miR-484, 642, 217 VEGFB and VEGFR2 N/I (30)
N/I, not identified.
with EMT phenotype such as SRY-related high-mobility group
box (SOX4) and hypoxia-inducible factor-1α(HIF-1α). Accord-
ing to this study, loss of HIF-αdecreases slug expression through
proteasome-mediated degradation, whereas EGFR is inhibited by
knockdown of SOX4 (14).
In addition, miR-200 family including miR-200a, b, c, miR-141,
and miR-429 are all dysregulated in OC cells undergoing EMT.
For instance, the expression levels of miR-141 and miR-429 were
significantly lower in mesenchymal-like and more metastatic HEY
cells compared with epithelial-like and less invasive OVCAR3 cells.
Forced overexpression of miR-429 and miR-141 in HEY cells was
able to repress the signature characteristics of mesenchymal-like
cells but activate those of epithelial-like cells (15). This finding
indicates that miR-200 family not only inhibits CSC phenotyp-
ical formation but also acts as a gatekeeper to prevent OC cells
from detaching and intravasation. Interestingly, cancer-associated
miRs are often found in downstream of tumor suppressors or
oncogenes. For example, miR-34, a tumor suppressor, is trans-
activated by P53 (22). The expression of miR-34 is lower in OC
compared with normal tissue and is further down-regulated with
disease progression. Reconstitution of miR-34 results in decreased
proliferation, progression/invasion, and reversal of EMT (23).
Although most of miRs uncovered in ovarian EMT confer repres-
sive effects on EMT (i.e., MET), miR-20a has been shown to down-
regulate the expression of PTEN, a tumor suppressor and conse-
quently render ovarian CSC properties and EMT phenotypical
transformation (21).
microRNAs AND EXTRACELLULAR MATRIX MODIFICATION
Extracellular matrix (ECM) is composed of interlocking fibrous
proteins and glycosaminoglycans (GAGs), which provide struc-
tural and biochemical support for cells surrounded as illustrated
in Figure 1D. Tumors achieve invasion and metastasis through
modulating the microenvironment, in particular the ECM that
surrounds them (31–33). Aberrant expression of miRs could ren-
der tumor cells metastatic capacity through destruction of ECM as
shown in Table 1. For example, in glioma, miR-21 was suggested
to be an oncomiR because of its ability to repress the expression
of RECK and TIMP3 which are the inhibitors of matrix met-
alloproteinase (MMPs), thereby conferring the metastatic capa-
bilities (34). In human hepatocellular cancer (HCC), miR-21
also repressed PTEN expression and consequently increased focal
adhesion kinase phosphorylation and expression of matrix MMP-
2 and 9 (35). In addition to the regulation of canonical MMPs,
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Wang et al. miRs in ovarian cancer metastasis
some miRs are involved in cell–ECM interactions and expression
of ECM components. The glycoprotein tenascin C (TNC), a pro-
tein that inhibits the interaction between cell–ECM, was shown to
be a target of miR-355, and loss of miR-355 potentiatedtumor cells’
metastatic abilities (31). miR-29c directly repressed the expres-
sion of ECM-related genes such as laminin gamma 1 and multiple
collagens in nasopharyngeal carcinomas (NPCs) (32).
While the involvement of miRs in ECM formation and mainte-
nance is increasingly reported in breast cancer, glioma, and HCC,
the study in OC is still emerging. Interestingly, Sorrentino et al.
demonstrated that miR-355, which has been shown to inhibit
tumor metastasis by targeting TNC expression (31,33,36) was
down-regulated in three OC cell lines resistant to paclitaxel and
one cell line resistant to cisplatin, suggesting potential connection
between ECM alteration and EMT transformation that can lead
to chemo-resistance in OC (24).
microRNAs AND ANGIOGENESIS
Tumor angiogenesis is the vital process through which tumors get
further progressed and transformed from benign states to malig-
nant states. It is contentious whether angiogenesis is necessary to
tumor metastasis, but this handy process during tumor progres-
sion facilitates cells to reach and disseminate via blood circulation
(19,20,29) as illustrated in Figure 1C. In response to hypoxic con-
ditions, tumor cells during progression increase the expression of
miRs that sustain tumor growth and neo-angiogenesis, or decrease
the expression of miRs that repress neo-angiogenesis. For exam-
ple, the up-regulated miR-27a is able to inhibit ZBTB10 expression
and thereby indirectly regulates the expression levels of vascular
endothelial growth factor (VEGF) and VEGF receptor (VEGFR).
Conversely, miR-16, miR-15b, miR-20a, and miR-20b that repress
angiogenesis through modulation of VEGF and VEGFR levels are
consistently down-regulated in tumor cells. More recent studies
shed light on the roles of miRs in OC angiogenesis as summarized
in Table 1.
Xu et al. has shown that miR-145 was repressed in OC tis-
sues and cell lines due to its inhibitory effect on neo-angiogenesis
(29). A mechanistic study demonstrated that miR-145 was able to
repress p70S6K1 expression and thereby inhibited the expression
of both HIF-1αand VEGF. Similarly, miR-125b and miR-199a
were shown to be tumor-suppressive miRs by targeting HIF-1α
and VEGF and consequently reduced angiogenesis (20). In addi-
tion, HER2 and HER3 were suggested to be the direct targets of
miR-125b and miR-199a because overexpression of miR-125b and
miR-199a led to the failure of angiogenesis in xenograft mod-
els of OC, which is mediated by these two genes. Some miRs
such as miR-217, miR-484, and miR-642 have been shown to
directly modulate VEGFB and VEGFR2 pathways and predict
tumor chemo-resistance (30). Ablation of miR-27a also repressed
the expression of VEGF as well as Cox2 and Sp1. In particular,
miR-27a appears to play a central role in follicle-stimulating
hormone (FSH)-mediated angiogenesis in OC (19).
CIRCULATING microRNAs IN OVARIAN CANCER
Ovarian cancer is the most fatal gynecologic malignancy among
women in the Unites States. Current treatment is based on surgery
in combination with platinum-based chemotherapy. However,
once patients with OC are diagnosed at advanced stages, there
is limited availability of effective treatments. Therefore, the dis-
covery and adoption of early detection biomarker is critical for
the improved outcome. Cancer antigen 125 (CA-125) is the most
commonly used marker to detect OC, monitor the response of
OC to treatment, and predict patients’ prognosis after treatment.
However, due to its lack of sensitivity, CA-125 is only detectable
when patients are advanced to late stages. Furthermore, serum
CA-125 levels are non-specifically elevated in patients with other
cancers including cancers of lung, breast, and gastrointestinal
tract (2–6).
Lawrie et al. first described that the serum levels of miR-21
were correlated with relapse-free survival in patients with diffuse
large B-cell lymphoma (37). Subsequently, serum miR-141 levels
have been used to monitor patients with prostate cancer. Using
mouse prostate cancer xenograft models, the presence of tumor-
derived miR-141 in mouse serum was confirmed (38). Chen et al.
compared miR expression signature in patients with lung and col-
orectal cancer with healthy subjects and found that miR-25 and
miR-223 were overexpressed in cancer patients (39,40). Circulat-
ing miRs were also detected in patients with HCC, non-small-cell
lung cancer (NSCLC), prostate cancer, breast cancer, and gas-
tric cancer (41). Among patients with OC, miR-21, miR-29a,
miR-92, miR-93, miR-99b, miR-126, miR-127, and miR-155 were
aberrantly expressed in blood compared to healthy controls (40).
Because miRs were detected in patients’ serum even at early
stage of various cancers, miR signatures of tumor-derived exo-
somes or other microvesicles have been proposed as diagnostic
biomarkers of many cancers (42–44). Unlike those synthetic RNAs
that are degraded by RNases in blood, miRs are incorporated
into a membrane-enclosed complex and resistant to RNases in
plasma. In addition, the levels of miRs in serum have been shown
to be particularly stable against temperature and pH changes,
rendering miRs as reliable diagnostic, prognostic, and predictive
biomarkers (39,45).
CONCLUSION AND PERSPECTIVE
Metastasis is a multifactorial complex process in which tumor
cells gain CSC-like properties and undergo EMT phenotypical
changes through degrading ECM to disseminate into non-adjacent
tissues with bloodstream. microRNAs play central roles in initia-
tion, progression, invasion, and metastasis of cancer. While most
miR signatures in cancers are involved in both tumor growth and
metastasis, there are a few groups of them that were important for
tumor metastasis, while exerting no effects on tumor proliferation
(46). For example, miR-22 has just been linked to progression of
OC to late stages, but no effects on cell viability and apoptosis (25).
miR-150 and miR-146a are highly expressed in omental lesion
compared to primary tumor sites and enhance spheroid forma-
tion to promote OC metastasis and chemoresistance to cisplatin
(26). In addition, miR-124 is down-regulated in clinical OC speci-
mens compared to adjacent normal tissues and correlates with the
severity of metastasis both in vivo and in vitro (28). miR-182 is
shown to be oncogenic, particularly in high-grade serous ovarian
carcinoma (HG-SOC). miR-182 targets breast cancer 1 (BRCA1)
and metastasis suppressor 1 (MTSS1) to impair the repair of DNA
double-strand breaks, but simultaneously enhances the expression
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Wang et al. miRs in ovarian cancer metastasis
of high-mobility group AT-hook2 (HMGA2) (27). Taken together,
it is well-appreciated that miRs are able to alter metastasis status
by modulating the expression of genes involved in CSC transfor-
mation, EMT, angiogenesis, and ECM as shown in Table 1 and
Figure 1. As we also reviewed the research on circulating miRs,
miRs can be promising biomarkers for OC. Further studies are
warranted to investigate their potential diagnostic and therapeutic
utilities for patients with OC.
ACKNOWLEDGMENTS
We thank editors for inviting us to write this mini-review. Due to
space restrictions, the authors cannot cite many important liter-
atures in this field. The authors apologize to all colleagues whose
work contributed significantly. This work was supported by Geor-
gia Regents University Departmental Start-up Fund andAmerican
Heart Association Grant-in-Aid 12GRNT12100048 and Scientist
Development Grant 14SDG18970040 to Il-man Kim.
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Conflict of Interest Statement: The authors declare that the researchwas conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 21 April 2014; paper pending published: 19 May 2014; accepted: 27 May
2014; published online: 10 June 2014.
Citation: Wang Y, Kim S and Kim I (2014) Regulation of metastasis by microRNAs in
ovarian cancer. Front. Oncol. 4:143. doi: 10.3389/fonc.2014.00143
This article was submitted to Molecular and Cellular Oncology, a section of the journal
Frontiers in Oncology.
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Frontiers in Oncology | Molecular and Cellular Oncology June 2014 | Volume 4 | Article 143 | 6