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Cancer Cell & Microenvironment 2015; 2: e670. doi: 10.14800/ccm.670; © 2015 by Changhe Jia, et al.
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RESEARCH HIGHLIGHT
Emerging links of CD151 and integrins to tumorigenesis and
EMT induction in ovarian cancer
Changhe Jia1,2,*, Sonia F. Erfani2,3,* Zeyi Liu4,*, Yecang Chen2,*, Michael Lu5, Jian-An Huang4, John R. van Nagell2, David
M. Kaetzel6, Binhua P Zhou2, Xiuwei H. Yang2,7
1
Department of Gastroenterology, Henan Provincial People's Hospital, Zhengzhou, Henan Province, P.R. China
Departments of Pharmacology & Nutritional Sciences, Molecular and Cellular Biochemistry, Department of Obstetrics and
Gynecology, and Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, USA
3
Department of Pharmacy Practice & Science, University of Kentucky College of Pharmacy, Lexington, Kentucky, USA
4
Department of Respiratory Medicine, the First Affiliated Hospital of Soochow University, Suzhou, P. R. China
5
Department of Biomedical Science, Florida Atlantic University, Boca Raton, Florida, USA
6
Department of Biochemistry & Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA
7
Department of Pharmacology & Nutritional Sciences, and Markey Cancer Center, University of Kentucky College of Medicine,
Lexington, Kentucky, USA
*
These authors contributed equally to this work.
2
Correspondence: Xiuwei H. Yang
E-mail: [email protected]
Received: February 24, 2015
Published online: April 11, 2015
Ovarian cancer, primarily the epithelia-origin high-grade serous (HGS) type, is one of the most lethal
gynecological malignancies. Clinically, over 75% of newly diagnosed HGS ovarian cancer patients carry stage
III-IV diseases, and have less than 33% survival rate over a 5-year span. Current treatment of such aggressive
disease remains largely dependent on two types of chemotherapeutic drugs: Taxane- and platinum-based agents.
Thus, there is an imminent need for the improvement in the detection, diagnostic modalities and target-based
therapies against this malignant disease. The majorities of HGS ovarian tumors exhibit mutational inactivation
or loss of p53 and/or BRCA1/BRCA2 genes, thereby conferring strong genomic instabilities. As such, currently
available target–based therapies, such as inhibitors targeting ErbB receptors or Raf/Ras/MAPK- or
PI3k/Akt-dependent oncogenic pathways, display limited efficacy against HGS ovarian cancer. Our recent study
suggests that the malignancy of this aggressive disease, at least in part, is regulated by CD151 and its associated
laminin-binding (LB) integrins. Our clinical, functional and xenograft analyses consistently indicate that in
contrast to prior reports on the RGD-based integrins, CD151-LB integrin complexes play a strong suppressive
role in ovarian tumorigenesis and metastatic progression. In this short review/commentary, we will briefly
summarize our current understanding of integrin function and signaling in ovarian cancer. We will discuss the
emerging clinical significance and functional roles of CD151-LB integrin complexes in this disease. Finally, we
will provide an outlook of how studies of CD151-integrin complexes may shape our understanding of ovarian
cancer aggressiveness and facilitate the development of effective biomarkers and therapeutic targets.
Keywords: CD151; Integrin; EMT; Ovarian cancer; Slug; Wnt signaling
To cite this article: Changhe Jia, et al. Emerging links of CD151 and integrins to tumorigenesis and EMT induction in
ovarian cancer. Can Cell Microenviron 2015; 2: e670. doi: 10.14800/ccm.670.
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Cancer Cell & Microenvironment 2015; 2: e670. doi: 10.14800/ccm.670; © 2015 by Changhe Jia, et al.
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Overview of
malignancy
ovarian
cancer
genetics,
types
and
Epithelial ovarian cancer is one of the most fatal
gynecologic malignancies in the United States. More than
75% of high-grade serous (HGS) carcinomas, the most
common type of epithelial ovarian cancer, are diagnosed in
the late and highly aggressive stages [1]. Up to now,
cytoreduction (or tumor debulking) followed by adjuvant
chemotherapy, i.e., a combination platinum-and taxane-based
agents, is still the mainstay for management of advanced
ovarian cancer. The effectiveness of such clinical treatment is
often complicated by chemoresistance [2]. As such, patients
with ovarian cancer face a grim 5-year survival rate that is
below 33% [3,4]. Thus, there is an urgent need for the
development of more effective target-based therapies to
improve clinical outcomes of this disease.
Extensive genomic studies have unveiled high genetic
heterogeneity in HGS ovarian tumors. In particular, ovarian
tumors harbor extensive mutations or inactivation or loss of
p53 and BRCA1/2 genes, giving rise to high genomic
instability [5,6]. As a result, there are extensive chaotic
rearrangements of chromosome or gene structure in HGS
ovarian tumors, as reflected by massive gene amplification or
deletion or loss of heterozygosity (LOH) [7]. In contrast,
low-grade ovarian tumors are characterized by typical
oncogenic changes or activation of ErbB receptors and/or
Ras/MAPK and PI3K/Akt pathways [1]. The recent
development of antibodies and small molecule-based
inhibitors that target these oncogenic pathways provide great
promise for curative treatment of this subgroup of ovarian
cancer. By comparison, there is still lack of effective
therapeutic strategies for overcoming the lethality of HGS
ovarian cancer.
Based on gene expression profiling studies, HGS ovarian
tumors can be further divided into at least four subtypes:
mesenchymal,
differentiated,
immunoreactive,
and
proliferative [7]. There is increasing evidence that such
heterogeneous nature of HGS ovarian tumors is closely
associated with the epithelial-mesenchymal transition (EMT)
program [8-12]. Like other carcinomas, HGS ovarian tumors
undergo typical EMT process, which is featured with the loss
of epithelial cell-associated cell-cell contacts and the gain of
mesenchymal cell-linked cell-extracellular matrix (ECM)
interactions [9]. At the molecular level, this process is
accompanied by the altered expression of several key cell
adhesion molecules, namely of the cadherin and integrin
families [9]. These include the reduction of E-cadherin and a
concomitant increase in 5-integrin, N-cadherin, and their
ECM ligands (e.g., fibronectin, collagens) [13,14]. In line with
the pro-malignant nature of the EMT program, the
mesenchymal subtype among HGS ovarian cancer is
associated with strong tumor aggressiveness and worst
clinical outcomes [14].
Integrins and ovarian cancer malignancy
As a family of heterodimeric adhesion receptors, integrins
are widely recognized for their structural support of tissue
architecture and signaling function in diverse biological and
pathological processes [15]. Up to now, most integrin-related
studies of ovarian cancer have focused on the RGD-based
integrins, including v3 and 51, along with their ligands
(e.g., vitronectin and fibronectin) [16,17]. Functionally, these
molecules appear to promote ovarian tumor cell proliferation
and progression [18,19]. Also, such functional links involve an
enhanced tumor cell-ECM interactions and accelerated
remodeling of their microenvironments [9,20].
By far, the strongest link of integrins to ovarian cancer
malignancy is the extensive amplification of focal adhesion
kinase (FAK), a pivotal tyrosine kinase downstream of
integrin signaling. There is evidence that FAK is amplified in
more than 30% of ovarian tumors [21,22] and knockdown or
small molecule-based inhibition of this kinase effectively
impairs the proliferation of ovarian cancer cells [22,23]. Also,
some of these FAK inhibitors may act in synergy with
chemotherapeutic agents to disrupt the malignancy of ovarian
cancer [21,23]. Hence, the function and FAK-dependent
signaling of the RGD-based integrins are crucial to ovarian
tumorigenesis and progression.
Tumor-suppressing roles of CD151 and laminin-binding
integrins in HGS ovarian cancer
The laminin-binding (LB) integrins, including 31, 61,
71 and 64 integrins, are principal adhesion receptors for
normal or tumorigenic epithelial cells [24]. Compared to the
RGD-based integrins, however, this subset of integrins has
received limited attention regarding their functional and
signaling roles in ovarian cancer. We recently attempted to fill
this void by evaluating clinical significance and functional
roles of these adhesion receptors in such disease, particularly
in the context of their associated CD151.
CD151 is a member of the tetraspanin family and acts as a
master regulator of LB integrin function and signaling in
normal or tumorigenic epithelia cells. Notably, in
well-transformed or malignant carcinoma cells with minimal
or no expression of E-cadherin (e.g., MDA-MB-231 and
HT1080 cells), CD151 actively promotes tumor cell adhesion,
motility and invasion over laminin matrices [25-29]. CD151 also
activates multiple signaling pathways or gene expression,
including those mediated by PKC-, FAK-, Ras/MAPK, RTKs
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and TGF- [28,30-34]. At molecular level, CD151 seems to drive
the function and signaling of LB integrins by enhancing their
molecular clustering on the cell surface within the palmitateand tetraspanin-enriched membrane microdomains [26,35-37].
There is increasing evidence, however, that CD151 and its
associated LB integrin may also suppress tumorigenesis or
metastasis in certain cancer types, particularly endometrial,
prostate and skin cancer [8,38-40] .
Our recent study with tissue microarray-based patient
samples indicates that CD151 expression is negatively
correlated with the aggressiveness of ovarian cancer [8]. In
line with this clinical link, disruption of CD151 enhances
ovarian tumor cell proliferation and growth or ascites
production in immuno-deficient mice [8]. In particular, the
tumors developed from the injected human ovarian tumor
cells recapitulated the typical histomorphologic features of
HGS ovarian cancer. Thus, our study for the first time
provides crucial clinical and functional evidence of CD151
as a key player in ovarian cancer progression. Intriguingly,
prior to our study, there were reports that CD151 and its
associated 31 or 64 integrin promoted ovarian cancer
cell invasiveness [41]. In fact, we did find that loss of CD151
impaired EGF-stimulated motility and invasion of ovarian
cancer cells as seen in other cancer type [26,30]. However, our
further mechanistic analyses shed new light on such dilemma
of CD151-LB integrin complex function in ovarian cancer.
Several lines of evidence in our recent study support the
notion that the tumor-suppressing function of CD151 in
ovarian cancer is largely attributed to its strong role in
stabilizing cell-cell contacts [8]. In particular, CD151 exhibits
basolateral distribution in ovarian tumors or their normal
counterparts (e.g., fallopian tube) (Fig. 1A). Such expression
pattern is also detected in cultured HGS ovarian tumor cell
lines (Fig. 1B) [8]. In fact, this type of CD151 distribution has
been linked to the integrity of cell-cell contacts in other types
of normal and malignant epithelial cells or endothelial cells
[42-47]. Also, similar distribution and functional links have long
been recognized for CD151-associated 31 integrin across
multiple types of carcinomas [42,48,49]. Furthermore, there is
evidence that 31 integrin is inversely correlated with the
metastatic potential [50,51]. In addition, 64 integrin is
implicated as a suppressor of tumorigenesis in the absence of
oncogenic H-RAS [52]. Collectively, our data and other studies
consistently suggest that during tumorigenesis and metastasis,
the functions of CD151 and LB integrins are oncogenic
context- and/or tumor stage-dependent.
Control of EMT and transcription factor Slug by
CD151-3β1 integrin complexes
One of the unexpected findings in our recent study is that
Figure 1. Expression and function of CD151-integrin
complexes in human serous-type ovarian cancer. A IHC
staining of CD151 in human ovarian tumors showing
epithelia-like (Case 1) or mesenchymal-like (Case 2)
morphologies. Scale bar: 100µm. B Immunofluorescence
images of E-cadherin protein on the surface of OVCAR5 cells
with or without Cd151 knockdown. Red- antibody staining;
Green: GFP. C Schematic illustration of function and signaling
of CD151-31 integrin complexes in HGS ovarian cancer.
CD151 ablation causes a partial reduction in E-cadherin
expression on the surface of ovarian cancer cells (~ 33% by
FACS analysis) (Fig. 1B) [8], in contrast to the prior analysis of
skin squamous carcinoma cells [42]. Such observation also
differs from the formation of strong mesenchymal phenotype
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during the EMT process or tumor progression [10,53]. However,
our finding is consistent with the emerging notion that the
EMT may exist in a spectrum form in ovarian tumors,
according to recent analyses of a panel of cultured cell lines
[12]
. Also, CD151 disruption leads to a marked increase in the
expression or activation of Slug, a transcription factor known
to promote the EMT phenotype during a variety of
physiological or pathological processes [54,55]. In fact, Slug is
also widely regarded as a crucial driver of ovarian cancer
development and metastasis [13,20,56,57]. While multiple factors
or pathways have been linked to the induction of Slug [55,58],
our study suggests that the induction of Slug upon CD151
removal may be attributable to the disruption of cell-cell
contacts or reduced expression of E-cadherin (Fig. 1B). Also,
the change in Slug protein may result from an increased
protein stability, rather than mRNA, according to our recent
studies of mammary epithelial cells [8, 60]. Thus, our recent
findings provide strong evidence that CD151-3β1 integrin
complexes repress the EMT process in ovarian cancer by
affecting the expression or activation of transcription factor
Slug.
It is also worth noting that the ECM organization in ovarian
carcinoma cells is altered upon CD151 disruption, particularly
a concomitant increase in fibronectin deposition [42,44]. The
fibronectin-51 integrin engagement has been shown to be
more effective in activating RhoA in carcinoma cells,
compared to the laminin-LB integrin interaction [60]. In light of
the strong pro-malignant function and signaling of fibronectin
and associated 51 integrin interaction in ovarian cancer [18],
CD151-LB integrin complexes may also exert
tumor-suppressing function by sequestering the signaling of
the fibronectin-51 integrin-RhoA axis.
Future functional and signaling studies of CD151 and
laminin-binding integrins in ovarian cancer
Potential feedback of Wnt signaling upon disruption of
CD151-integrin complexes. Our recent Slug-based
observations also imply that CD151-integrin complexes may
impact the aggressiveness of ovarian cancer at transcriptional
level. In fact, we detect a strong functional link of
CD151-31 integrin complexes to the canonical Wnt
signaling [8]. To certain degree, this observation is in line with
recent signaling analyses of CD9 and other tetraspanins
[35,61,62]. Intriguingly, CD151 ablation also leads to an
upregulation of KIAA1199 and RNF43, two newly identified
negative regulators of Wnt signaling [63,64]. Currently, we are
investigating whether such molecular changes constitute a
feedback loop of activated Wnt signaling in response to
impaired cell-cell contacts or Slug expression upon the
disruption of CD151 or LB integrins.
Downstream effectors of CD151-integrn complexes as
potential biomarkers or therapeutic target. One of interesting
findings in our ovarian cancer study is the strong
upregulation of MUC5AC upon CD151 ablation [8]. As a large
secretory glycoprotein of the mucin superfamily, MUC5AC
is strongly elevated in HGS ovarian tumors [65,66]. It is also
readily detectable in patient’s urinary or blood samples or
condition medium of cultured ovarian cancer cells [67,68]. By
comparison, CA125/MUC16, a mucin serving as a biomarker
for ovarian cancer diagnosis or detection, is more broadly
expressed in ovarian tumors, ranging from the borderline to
late-stage [66]. Moreover, MUC5AC is implicated in
promoting tumor cell adhesion and signaling [69]. Based on
these observations, we are currently testing if MUC5AC
serves as a candidate diagnostic or prognostic biomarker for
HGS ovarian cancer.
Concluding remarks
Unexpectedly, our recent study suggests that a subset of
integrins and associated proteins, particularly LB integrins,
and their associated CD151, play a strong suppressive role in
highly aggressive ovarian cancer by impacting the EMT and
tumorigenic processes (Fig. 1C). This is also one of very few
functional analyses of these adhesion molecules in such
disease. Importantly, our findings raise a strong possibility
that genetic alteration or disruption of CD151-31 integrin
complexes may cause a concomitant activation of the
canonical Wnt signaling and transcription factor Slug, thereby
driving tumorigenesis and metastasis (Fig. 1C). With evidence
accumulating in this direction, we will begin to gain more
mechanistic insights into the unusual aggressiveness of human
ovarian cancer, and develop more effective biomarkers or
therapeutic strategies for the detection and treatment of such
malignant disease.
Conflicting interests
The authors have declared that no competing interests
exist.
Acknowledgments
XH Yang was supported in part through DOD Ovarian
Cancer Research Program W81XWH-08-1-0120, S. G.
Komen for the Cure career catalyst award, NIH
COBRE/pilot project fund and a pilot project grant from
American Cancer Society #IRG 85-001-25.
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