International Journal of

Molecular Sciences

Review
Galectin-7 in Epithelial Homeostasis and Carcinomas
Tamara Advedissian, Frédérique Deshayes and Mireille Viguier *
Team Morphogenesis, Homeostasis and Pathologies, Institut Jacques Monod, UMR 7592 CNRS—University
Paris Diderot, Sorbonne Paris Cité, 15 rue Hélène Brion, 75013 Paris, France; tamara.advedissian@ijm.fr (T.A.);
frederique.deshayes@ijm.fr (F.D.)
* Correspondence: mireille.viguier@univ-paris-diderot.fr

Received: 23 November 2017; Accepted: 14 December 2017; Published: 19 December 2017

Abstract: Galectins are small unglycosylated soluble lectins distributed both inside and outside the
cells. They share a conserved domain for the recognition of carbohydrates (CRD). Although galectins
have a common affinity for β-galatosides, they exhibit different binding preferences for complex
glycans. First described twenty years ago, galectin-7 is a prototypic galectin, with a single CRD,
able to form divalent homodimers. This lectin, which is mainly expressed in stratified epithelia,
has been described in epithelial tissues as being involved in apoptotic responses, in proliferation
and differentiation but also in cell adhesion and migration. Most members of the galectins family
have been associated with cancer biology. One of the main functions of galectins in cancer is
their immunomodulating potential and anti-angiogenic activity. Indeed, galectin-1 and -3, are
already targeted in clinical trials. Another relevant function of galectins in tumour progression
is their ability to regulate cell migration and cell adhesion. Among these galectins, galectin-7 is
abnormally expressed in various cancers, most prominently in carcinomas, and is involved in cancer
progression and metastasis but its precise functions in tumour biology remain poorly understood.
In this issue, we will focus on the physiological functions of galectin-7 in epithelia and present the
alterations of galectin-7 expression in carcinomas with the aim to describe its possible functions in
tumour progression.

Keywords: galectins; galectin-7; epithelia; carcinoma

1. Introduction
Galectins are a family of soluble lectins, which possess a large variety of ligands and functions.
Among the galectins, galectin-7 presents a unique tissue-specific expression pattern and participates in
diverse biological processes, notably in the regulation of epithelial homeostasis. In this review, after
discussing general information about the galectin family, we will present galectin-7 expression profile
and structure. Then, we will focus on the role of galectin-7 in epithelial homeostasis, in cell adhesion
and migration by presenting the results obtained both in animal models and cell lines. Finally, we will
address the association of galectin-7 with carcinoma and its putative function in cancer progression.

1.1. Galectins
Galectins were identified in the 1970s [1,2] and formerly named S-type lectins, due to their
solubility and the sulfhydryl-dependency of the first galectins discovered [3], but their nomenclature
became systematic in 1994. Since then, they were ranked according to their order of discovery [4].
Several galectins are expressed in the same species with up to 16 galectins identified in mammals
and 12 in humans [5–7]. Galectins are a family of proteins characterized by a common affinity for
β-galactoside containing carbohydrates and an evolutionary conserved Carbohydrate Recognition
Domain (CRD) [4]. The different galectins do not possess any signal peptide or any anchoring domain
and are synthesized by the free polysomes in the cytosol [7]. The unique exception is galectin-3,

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Int. J. Mol. Sci. 2017, 18, 2760 2 of 17

which possess a NES (Nuclear Export Signal) [8] and a NLS (Nuclear Localization Signal)-like motif
with similarities with the NLS of p53 and c-Myc [9]. The galectins are secreted by an unconventional
pathway and thus can be localized in the extracellular compartment [10,11]. However, they are also
found in the cytosol, in the nucleus, or even in the mitochondria [11,12].
Moreover, while some galectins such as galectin-1 and galectin-3 are widely expressed, other
family members have a more restricted tissue localisation. Hence, galectin-2 expression is limited to
digestive epithelia [13] and galectin-7 is preferentially expressed in stratified epithelia [14].
Galectin sequences are similar from the lower invertebrates to mammals. The common basic
structure of the galectin domain is composed of about 130 amino acids organised in two β-sheets
containing five (F1–F5) and six (S1–S6) anti-parallel β-strands forming a jellyroll topology (see
galectin-7 structure in Figure 1a) [4,15]. Seven carbohydrate-binding amino acids in strands S4,
S5 and S6 are essential for the specific binding of β-galatosides [16] and are highly conserved among
galectins [17,18]. These amino acids are encoded by three consecutive exons in mammalian galectins
and form a characteristic sequence of galectins called the CRD [4].
According to the structural organization of their CRD, galectins can be classified into 3 subtypes.
Hence, “proto-type” galectins, are composed of a single galectin domain that is able to dimerize
(galectin-1, -2, -5, -7, -10, -11, -13, -14, and -15) whereas “tandem repeat-type” galectins possess a single
polypeptide chain with two CRDs connected by a linker peptide (galectin-4, -6, -8, -9, and -12). The
“chimera-type” subtype, with galectin-3 being the unique member, is constituted of one C-terminal
CRD linked to a N-terminal non-lectinic domain [19,20].
Another classification of galectins, which is based on the determination of two CRD subtypes,
also exists and refers to the evolution of galectins. The CRDs are thus defined according to the relative
position of intron/exon corresponding to the sequence of the F4 or F3 β-sheet. Indeed, among the 3
exons encoding the CRD, there are two subtypes of the second exon, also called “W” exon because of
the presence of a highly conserved tryptophan residue. One of the “W” exon ends within the sequence
encoding the F4 β-strand and the other ends within the sequence encoding the F3 β-strand. These two
subtypes have been called respectively F4-CRD and F3-CRD. Prototype galectins can belong to the
F4-CRD subtype (e.g., galectin-7, galectin-10) or to the F3-CRD subtype (e.g., galectin-1, galectin-2)
and galectin-3 contains a F3-CRD. The tandem-repeat galectins contain both a F4-CRD and a F3-CRD
subtypes [7,20].
Thanks to their CRD, galectins recognize oligosaccharides present in proteins, lipids or microbial
molecules. The minimal ligand recognized by galectins is N-Acetyl-Lactosamine (LacNAc), a
disaccharide found on both N- and O-glycans [7,21]. However, galectins have a selective affinity for
sugars with complex organisation according to their structure and composition: amount of branching,
of LacNAc repeats (poly-LacNAc) or the presence of terminal saccharides such as sialic acid or
fucose [21–23]. These differences enable the specific affinity of a given galectin for its ligand. In general,
the affinity of galectins for complex carbohydrates increases with the number of LacNAc repeats and
the number of branches. Hence the major ligands of galectins are N-glycans [21,24].
As a consequence, galectins can bind multiple glycosylated partners, either glycoproteins or
glycolipids. Due to their multivalence, they form networks of molecules termed “lattice “ [25,26]. In
addition to binding to glycans on glycoconjugates, galectins interact with unglycosylated intracellular
but also extracellular ligands. As an illustration, galectin-1 has been shown to interact directly with
the pseudo-light chain λ5 of the pre-BCR (B Cell Receptor) [27] and galectin-7 with Bcl-2 [12] or
E-cadherin [28].
Due to their diversity of localisation and their various partners, the different members of the
galectin family display a striking functional diversification. In particular, they are involved in
intracellular trafficking as well as in cell adhesion and cell migration, in the regulation of the immune
system or even in mRNA splicing [11]. Galectins can also affect cell signalling and impact development
and tissue homeostasis leading to the emergence of pathologies such as cancer [7,25,29].
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2760 3 of 17

Figure 1. (a) Representation of the crystal structure of galectin-7 in complex with LacNAc (PBD
Figure 1.
4XBQ) (a) Representation
[30]. Carbohydrates ofarethe crystal structure
recognized by theof galectin-7
residues in complex
H49, N51, R53,with
N62,LacNAc
W69, E72(PBD 4XBQ)
and R74
forming the CRD. (b)
[30]. Carbohydrates Crystal
are structure
recognized of homodimeric
by the residues H49, galectin-7
N51, R53, (PBD 1BKZ)
N62, W69, [18]
E72 illustrating
and the
R74 forming
“back-to-back” arrangement
the CRD. (b) Crystal of galectin-7
structure dimers with
of homodimeric the two
galectin-7 CRD
(PBD orientated
1BKZ) in the opposite
[18] illustrating direction.
the “back-to-
Structures obtained from
back” arrangement www.rcsb.org.
of galectin-7 dimers with the two CRD orientated in the opposite direction.
Structures obtained from www.rcsb.org.
1.2. Galectin-7
1.2. Galectin-7
The galectin-7 gene was simultaneously discovered by Madsen and colleagues [31] and Magnaldo
The galectin-7
and colleagues [32] togene was simultaneously
be expressed in the epidermis, discovered
respectively by as Madsen
a protein and colleagues
repressed during [31] and
Simian
Magnaldo and colleagues [32] to be expressed in the epidermis, respectively
Virus-40 (SV-40)-mediated transformation of keratinocytes and as a protein differentially expressed in as a protein repressed
during keratinocytes
normal Simian Virus-40 and in(SV-40)-mediated
squamous cancertransformation
cells which failed of tokeratinocytes
complete terminal and askeratinocyte
a protein
differentially expressed
differentiation. This lectininis normal keratinocytes
mostly expressed and in epithelia
in stratified squamous cancer
notably in cells which failed
the epidermis (whereto
complete terminal keratinocyte differentiation. This lectin is mostly
galectin-7 is found both in interfollicular region and in hair follicles), the oesophagus, the tongue, theexpressed in stratified epithelia
notably
anus, theinlips
the andepidermis (where
the cornea galectin-7
[14,33,34]. is found both
However, in interfollicular
galectin-7 expression regionhas also andbeenin hair follicles),
described in
the oesophagus, the tongue, the anus, the lips and the cornea
thymic Hassall’s corpuscles [14], in sebaceous glands [33] and in myoepithelial cells from the mammary [14,33,34]. However, galectin-7
expression
epithelia hasGalectin-7
[35]. also beenhas described in thymic
also recently beenHassall’s
detected in corpuscles
the gingiva [14], in sebaceous
[36]. Importantly, glands [33] and
its expression
in induced
is myoepithelial
by p53cells and from the mammary
Ultra-Violet B (UVB)epithelia
light [37]. [35]. Galectin-7
Galectin-7 has alsoby
is secreted recently been detected
keratinocytes in
into their
the gingiva [36]. Importantly, its expression is induced by p53 and
culture medium despite the fact that, as all the galectins, it does not possess a typical secretion signalUltra-Violet B (UVB) light [37].
Galectin-7
peptide [31].is However,
secreted by keratinocytes
galectin-7 is alsointo
found their culture
in the cytosol,medium despite theand
in mitochondria factthethat, as all but
nucleus, the
galectins,
its function it does
in thenot possess
nucleus is alargely
typicalunknown.
secretion signal
Diverse peptide
studies[31]. However,
suggest galectin-7 isfunction
an intracellular also found of
in the cytosol, in mitochondria and the nucleus, but its function in the
galectin-7 as for example in the regulation of keratinocyte proliferation and differentiation through the nucleus is largely unknown.
Diverse
c-Jun studies suggest
N-terminal an intracellular function
Kinase (JNK1)–miR-203-p63 pathway of galectin-7
(see below) as [38].
for example
Galectin-7 in expression
the regulation of
can be
keratinocyte proliferation and differentiation through the c-Jun
induced via p53 or TNFα activation pathways, and both wild type and p53 mutants harbouring “hot N-terminal Kinase (JNK1)–miR-203-
p63 pathway
spot” point mutation(see below) [38].galectin-7
bind the Galectin-7 expression
promoter [39].can be induced
In addition, via p53
Nuclear or TNFα activation
Factor-kappa B (NF-κB)
pathways,
also binds to and theboth wild type
galectin-7 promoter and [39].
p53 mutants harbouring “hot spot” point mutation bind the
galectin-7 promoter
Galectin-7 [39].present
is widely In addition, Nuclearand
in mammals Factor-kappa B (NF-κB)has
only one orthologue also
been binds to the outside
described galectin-7 of
promoter [39].
the mammalian lineage in anol lizards [40]. Interestingly, a copy-number variation has been pointed
out forGalectin-7
galectin-7 is widely
for whichpresent
a singlein mammals
copy of two andgenes
only one has orthologue
been identified has beennotably described outside
in the human,
cow and dog genome [40]. The LGALS7 and LGALS7B genes have been duplicated in tandembeen
of the mammalian lineage in anol lizards [40]. Interestingly, a copy-number variation has but
pointed
in oppositeoutdirection
for galectin-7and areforfound
whichina chromosome
single copy of19two genes has
in humans [40].been
Both identified
genes encode notably in the
identical
human, cow
galectin-7 and dog
protein butgenome [40]. The LGALS7
exhibit different putative and LGALS7B factors
transcription genes have beensites
binding duplicated
in theirin tandem
promoter
but in opposite direction and are found in chromosome 19 in humans
sequence suggesting differences in expression regulation [40]. It has been hypothesized that galectin-7 [40]. Both genes encode
identical
could come galectin-7 protein butofexhibit
from a duplication galectin-4different
[20] which putative transcription
is present factors binding
in its neighbourhoods as asites in their
single copy.
promoter sequence suggesting differences in expression regulation
Galectin-7, as other prototypic galectins, is able to form homodimers but with a different [40]. It has been hypothesized
that galectin-7
topology. Indeed, could come
despite from homologies
sequence a duplication withofother galectin-4
prototypic [20]galectins
which is such present in its
as galectin-1
neighbourhoods
or galectin-2 thatasassociate a single copy.
in dimer in a “side-by-side” organisation, galectin-7 form homodimer
Galectin-7, as other
through a “back-to-back” arrangement prototypic galectins,
giving is riseable
to atolargerform dimer
homodimers
interfacebut with a different
compared to other
topology. Indeed, despite sequence homologies with other prototypic galectins such as galectin-1 or
Int. J. Mol. Sci. 2017, 18, 2760 4 of 17

Int. J. Mol. Sci. 2017, 18, 2760 4 of 17

galectin-2 that associate in dimer in a “side-by-side” organisation, galectin-7 form homodimer
through a “back-to-back” arrangement giving rise to a larger dimer interface compared to other
prototypic galectins
galectins (Figure
(Figure 1b)1b)[18,41].
[18,41].This
This difference
difference in in structural
structural arrangement
arrangement suggests
suggests thatthat
the
the glycoconjugate
glycoconjugate bridging
bridging activity
activity of of galectin-7
galectin-7 maydiffer
may differfrom
fromother
other prototypic
prototypic galectins. The
substitution at position 74 of an arginine by a serine serine inhibits
inhibits the
the carbohydrates-binding
carbohydrates-binding activity of
galectin-7 but does not alter the capacitycapacity of
of galectin-7
galectin-7 to
to form
form homodimers
homodimers in in solution
solution [42].
[42]. This
indicates that
that binding
binding toto oligosaccharides
oligosaccharidesisisnotnotrequired
requiredforforgalectin-7
galectin-7totoform
formhomodimers
homodimers even
even if
if
it itcan
canslightly
slightlymodify
modifyits itsconformation
conformation andand influence
influence the dimers’ stability
stability [43,44].
[43,44]. Regarding
carbohydrate binding, galectin-7 displays preferential binding to internal or terminal LacNAc repeat
carried by N-glycan (Figure 1a) [21,22].
Multiple cellular functions have been attributed to galectin-7, most most of which are related to
epithelial integrity maintenance and will be described below. However, the established and putative
summarized in
cellular functions of galectin-7 are summarized in Figure
Figure 2.
2.

Figure 2. Schematic representation of known and putative functions of galectin-7. In addition to the
functions
functions ofofgalectin-7
galectin-7in cell proliferation,
in cell apoptosis,
proliferation, differentiation,
apoptosis, migration
differentiation, and adhesion
migration and described
adhesion
in this issue,
described few evidence
in this issue, fewhighlights
evidence other functions
highlights otheroffunctions
galectin-7ofingalectin-7
epithelia. inAsepithelia.
an illustration,
As an
galectin-7
illustration,has been shown
galectin-7 to interfere
has been shown with Transforming
to interfere Growth factorGrowth
with Transforming β (TGFβ) signalling
factor β (TGFβ)in
response to Hepatocyte Growth Factor (HGF) by promoting smad3 export from
signalling in response to Hepatocyte Growth Factor (HGF) by promoting smad3 export from the the nucleus and thus
preventing
nucleus and liver fibrosis
thus occurrence
preventing liver[45]. In addition,
fibrosis the commensal
occurrence bacteria Finegoldia
[45]. In addition, magna has
the commensal been
bacteria
described to adhere
Finegoldia magna has to thedescribed
been upper layers of the to
to adhere epidermis
the upper through binding
layers of of the adhesion
the epidermis throughbacterial
binding
protein F. magna Adhesion
of the adhesion Factor (FAF)
bacterial protein to galectin-7,
F. magna Adhesionindicating that galectin-7
Factor (FAF) can bind
to galectin-7, to ligands
indicating that
from microbial origin [46].
galectin-7 can bind to ligands from microbial origin [46].

2. Galectin-7 in Epithelial Homeostasis

Galectin-7 participates
participates in epithelial maintenance
maintenance by by regulating
regulating at least three key aspects of
epithelia homeostasis: cell
cell growth, cell differentiation
differentiation and
and apoptosis.
apoptosis. Nevertheless,
Nevertheless, the precise
mechanisms by which galectin-7 participate
participate in the regulation of these processes still remain to be
deeply.
decrypted more deeply.

2.1. Apoptosis
2.1. Apoptosis
Several studies have revealed
revealed a role of galectin-7
galectin-7 in
in the
the apoptotic
apoptotic response
response (Figure
(Figure 2)2) [34].
[34].
However, depending
depending on onexperimental
experimentalconditions,
conditions,galectin-7
galectin-7hashas been
been shownshown to beto either
be either
a pro-a
pro-apoptotic factor or an anti-apoptotic factor, indicating that galectin-7 activity in
apoptotic factor or an anti-apoptotic factor, indicating that galectin-7 activity in apoptosis variesapoptosis
varies according
according to the to the cellular
cellular contextcontext
and/orand/or the apoptotic
the apoptotic stimulus.
stimulus. First, it First, it was discovered,
was discovered, in the
in the epidermis, that UVB-induced sunburns increase galectin-7 expression in keratinocytes
epidermis, that UVB-induced sunburns increase galectin-7 expression in keratinocytes from human from
Int. J. Mol. Sci. 2017, 18, 2760 5 of 17

human skin ex vivo [37]. Remarkably, overexpression of galectin-7 occurs in apoptotic keratinocytes,
highlighting a possible association [37]. This has been demonstrated using mouse models lacking or
overexpressing galectin-7 in the epidermis in which both absence and excess of galectin-7 modify the
kinetics of the apoptosis response to UVB irradiation and induce premature apoptotic response [47,48],
pointing out the involvement of galectin-7 in the apoptosis process in vivo.
Addition of recombinant galectin-7 in absence of apoptotic stimuli is sufficient to induce apoptosis
in the T lymphocyte Jurkat cell line [41,49,50] and in freshly isolated human T cells [50], as previously
shown for other galectins [51]. Apoptosis induction by galectin-7 in Jurkat cells can be inhibited by
lactose addition, indicating that this function of galectin-7 relies on its lectin activity [50]. However, in
other cell types, addition of recombinant galectin-7 [50] or alterations of galectin-7 expression levels
alone [52,53] are not sufficient to induce apoptosis indicating that direct induction of apoptosis by
galectin-7 is restricted to T lymphocytes.
To investigate the function of galectin-7 in apoptosis, most researchers induce the ectopic
expression of galectin-7 in diverse cancer cell lines and examine the sensitivity of the cells to apoptotic
stimuli. As an illustration, de novo expression of galectin-7 in the cervical cancer HeLa cells and in the
colorectal adenocarcinoma DLD-1 cell line makes these cells more sensitive to the induction of apoptosis
by UVB irradiation or diverse chemical apoptotic stimuli [12,54–56]. Similarly, overexpression of
galectin-7 in ST88-14 cells, a sarcoma-derived cell line, in the cervical carcinoma siHa cells or in the
prostate cancer cells DU-145 results in an increased susceptibility of the cells to apoptotic stimuli [56–58].
Accordingly, galectin-7 downregulation in the cervical squamous carcinoma cells SiHa and C-33A
increases cell viability in response to the apoptosis-inducing chemotherapeutic agent paclitaxel [59].
All these studies indicate that galectin-7 has a pro-apoptotic effect in many cell types. However, in the
breast MCF-7 cancer cells or in the B16F1 melanoma cell line, ectopic expression of galectin-7 decreases
the cell sensitivity to apoptotic stimuli [42,60], indicating that galectin-7 can also, contrastingly, have
an anti-apoptotic effect.
Interestingly, the function of galectin-7 in apoptosis does not rely on its lectin activity and is
predominantly intracellular. Indeed, St-Pierre and colleagues have shown that the de novo expression
of a CRD-defective galectin-7 mutant harbouring a substitution of an arginine by a serine at position
74 (R74S mutant) had a similar effect to the expression of the wild type galectin-7 on apoptosis
susceptibility. These results were observed in both DU-145 prostate cancer cells where galectin-7 has
a pro-apoptotic effect [58] and in MCF-7 breast cancer cells where galectin-7 had an anti-apoptotic
function [42]. Nevertheless, how galectin-7 regulates apoptosis is still unclear. Kuwabara et al.,
reported that galectin-7-overexpressing cells exhibit increased cytochrome c release and amplified
JNK activation after apoptosis stimulation indicating that galectin-7 acts upstream of these two
pathways [54]. The mechanism by which galectin-7 participates in apoptosis could also be linked
to its interaction with the anti-apoptotic factor Bcl-2. Indeed, galectin-7 directly interacts with Bcl-2
in a carbohydrate-independent manner [12]. In accordance, overexpression of galectin-7 increases
cell apoptosis in response to a specific Bcl-2 inhibitor [56]. Remarkably, the R74S galectin-7 mutant,
which localizes far less efficiently to the mitochondria, still contributes to apoptosis regulation [58],
suggesting that galectin-7 may also function outside of the mitochondria.

2.2. Proliferation
Studies performed on diverse cell types, mostly cancerous cell lines, have demonstrated that
galectin-7 has a suppressive effect on cell proliferation (Figure 1). Indeed, ectopic expression or addition
of exogenous galectin-7 in the DLD-1 human colon carcinoma cell line [55] and the neuroblastoma
cells SK-N-MC, respectively [53], drastically reduced tumour cell proliferation. Consistently, galectin-7
knockdown in human keratinocytes results in a hyperproliferative phenotype [38]. However, ectopic
expression of galectin-7 in the B16F1 melanoma cell line did not affect cell growth [60] indicating that
cell context might be important for galectin-7 to modulate cell proliferation. Evidence obtained in vivo
in galectin-7-null mice indicates that galectin-7 is also involved in the regulation of cell growth during
Int. J. Mol. Sci. 2017, 18, 2760 6 of 17

stress responses. Indeed, galectin-7 deficiency induces enhanced cell proliferation after epidermal
injury or UVB irradiation of the skin [47].
The molecular mechanism by which galectin-7 participates in apoptosis and cell proliferation
remain to be clarified. However, galectin-7 could be an effector of the tumour suppressor gene p53.
Strikingly, galectin-7 expression is strongly induced by p53 [61] and lack of wild type p53 in human
keratinocytes cell lines prevents galectin-7 expression induction in response to UVB irradiation [37].

2.3. Differentiation
Both proliferating basal and quiescent differentiated suprabasal keratinocytes express and
secrete galectin-7 [14,31,32]. As a consequence, galectin-7 was described as a marker of stratified
epithelia but not as a marker of differentiation. However, some evidence has suggested a role of
galectin-7 in keratinocyte differentiation (Figure 2) such as its reduced expression after addition
of retinoic acid in cultured keratinocytes [32]. In addition, in keratinocytes cultured in vitro,
galectin-7 mRNA expression increases with the cell density, suggesting a potential link with epidermal
differentiation [62]. Regarding tumour biology, galectin-7 downregulation correlates with poor tumour
differentiation in bladder squamous cell carcinomas [63] and in vulvar squamous cell carcinoma [64].
Recently, Liu and colleagues produced the first mechanistic evidence of a function of galectin-7
in keratinocyte differentiation in vitro [38]. In fact, in the keratinocyte cell line HaCaT, galectin-7
knockdown reduces cell differentiation as assessed by the expression of keratins. Moreover, they
found that intracellular galectin-7 regulates keratinocyte differentiation through the JNK–miR-203-p63
pathway [38]. Indeed, their results indicate that galectin-7 interacts with JNK1 and prevents its
ubiquitination and subsequent degradation by the proteasome. Both galectin-7 and JNK1 induce
miR-203 expression and the subsequent inhibition of the transcription factor p63, an important
regulator of keratinocyte proliferation and differentiation [65].

3. Galectin-7 in Adhesion and Migration

In this section, we will describe current understanding of galectin-7 function in two interconnected
mechanisms: cell migration and adhesion (Figure 2). Both processes are required for tissue maintenance
and are central in tumour biology. As a consequence, modification of cell migration and adhesion
characteristics can promote cancer progression.

3.1. Adhesion
Several galectins have been implicated in cell–cell or cell–ECM (Extra-Cellular Matrix) adhesion
and thus, galectins are considered as a family of adhesion-modulating proteins [66]. However,
depending on conditions (i.e., galectin considered, galectin concentration or cell types) galectins
can either favour or prevent interactions with either the substrate or the neighbouring cells. Regarding
galectin-7, its subcellular localisation is enriched at cell-cell contacts in the suprabasal layers of human
and mouse epidermis [31,47]. However, the potential role of galectin-7 in intercellular adhesion is
poorly documented. Recently, a few studies came out indicating that galectin-7 mediates cell-cell
adhesion. Indeed, in the uterus, Menkhorst and colleagues showed that galectin-7 is expressed in the
endometrium and influenced trophoblast-endometrial epithelia intercellular adhesion in vitro [67].
This function of galectin-7 in cell-cell adhesion may have a crucial impact during embryo implantation.
In addition, our team previously showed that galectin-7 interacts with the adherent
junctions-component E-cadherin in keratinocytes [48]. Interestingly, we recently demonstrated that
galectin-7 directly binds to the extracellular domain of E-cadherin in a glycosylation-independent
manner [28]. This interaction has a functional consequence on intercellular adhesion as galectin-7
knockdown in HaCaT keratinocytes importantly reduces adherent junction-mediated adhesion [28].
Focusing on the underlying mechanisms, we demonstrated that galectin-7 stabilises E-cadherin at
the plasma membrane, preventing its endocytosis [28]. Interestingly, both galectin-7-null mice and
galectin-7-overexpressing mice show intercellular adhesion defects in the epidermis [48]. These results
Int. J. Mol. Sci. 2017, 18, 2760 7 of 17

are compatible with the current model for the regulation of adhesion by galectins. In this model, low
concentration of galectins will promote bridging of molecules by bi- or multivalent galectins and
favour adhesion. On the contrary, high amount of galectins will reduce their crosslinking properties
by decreasing the probability of simultaneous binding to two or more ligands and thus decreasing
adhesion [66]. As a consequence, absence or excess of galectins could have the same consequences.
Regarding the regulation of the adhesion to the ECM, a possible interaction between galectin-7
and β1-integrin has been suggested in polarised MDCK cells [68]. Consistently, the enhanced
endometrial wound repair induced by addition of exogenous galectin-7 is prevented by the blockade
of integrin–fibronectin interaction in vitro [69]. However, further investigations are needed to specify
the potential link between galectin-7 and integrins. Finally, galectin-7 could also participate in
cell-ECM adhesion by influencing Matrix Metallo-Proteinase proteins (MMP) expression. Indeed,
in lymphoma cells or in HeLa cells, exogenously added galectin-7 was able to enhance MMP-9
expression, suggesting a potential role for galectin-7 in the regulation of cell–ECM adhesion during
cancer dissemination [70,71]. Galectin-7 and MMP-9 also showed positive expression correlation in
human hypopharyngeal and laryngeal squamous cell carcinomas [72].

3.2. Migration
Galectin-7 has first been found to be involved in cell migration during epithelial wound healing
in mouse corneas where addition of exogenous galectin-7 accelerated re-epithelialisation after corneal
injury [73,74]. Simultaneous addition of lactose with exogenous galectin-7 prevented the increase
of healing rate due to galectin-7 supplement [73,74], suggesting that this function of galectin-7 in
corneal healing might be dependent on its binding to extracellular glycoconjugates. In mice corneas
and porcine skin epidermis, galectin-7 expression is increased following injury [73–76], indicating
that galectin-7 expression can be induced under stress conditions such as injury occurrence. Then,
studies performed in galectin-7-null mice revealed that galectin-7 is similarly involved in keratinocyte
migration during epidermal wound healing [47]. These mice displayed re-epithelialisation delay when
compared to Wild Type (WT) mice after tail superficial scratch. This role of galectin-7 in epidermal
wound healing is independent of its function in cell growth regulation but is related to a reduced
migratory potential of keratinocytes. Indeed, the delay in wound healing was observed as soon as 24h
h after injury, whereas no difference in cell proliferation was observed at this period in galectin-7-null
mice compared to WT mice. In addition, in the presence of the cell division inhibitor mitomycin, the
delay in wound healing was still observed in newborns’ skin explants from galectin-7-deficient mice
compared to WT mice [47]. Surprisingly, overexpression of galectin-7 in mice epidermis also delayed
wound closure after superficial epidermal injury [48], indicating that an optimal amount of galectin-7 is
required for proper keratinocyte migration. Focusing on the underlying mechanisms, we have recently
showed in vitro that galectin-7-depleted keratinocytes (HaCaT cells) have a reduced cell migration
speed but also an impaired collective behaviour resulting in a decreased migration efficiency [28].
These alterations have been hypothesized to be related to the defective adherent junction functioning
after galectin-7 silencing [28]. A role of galectin-7 in endometrial epithelial wound repair has also been
highlighted by in vitro assays [69].
The function of galectin-7 in collective cell migration is relevant in pathological conditions such
as cancer progression [34]. Indeed, in epithelial cancer, invasion processes of the surrounding healthy
tissue by tumour cells frequently exhibit collective invasion reminiscent of regenerative migration
of epithelial cells [77,78]. Accordingly, several groups reported an association between galectin-7
expression levels and cancer aggressiveness as we will discuss in the following section.

4. Galectin-7 and Carcinomas

Galectins are widely studied in cancer with several hundred references. Most members
have been implicated as being associated either as markers, diagnostic cues, candidate effectors
in cancer progression or modulators of treatment responses [29,79–84]. Interestingly, several
Int. J. Mol. Sci. 2017, 18, 2760 8 of 17

galectins are usually co-expressed by a single cell or tumour and may exert ill-defined synergistic or
compensatory properties.

4.1.Galectin-7 as a Tumour Progression Marker

Among these galectins, galectin-7, being expressed mostly in stratified epithelia, has been mainly
studied in carcinomas and its implications in cancer were referenced only in a few tens of published
articles. Among those, even fewer studies explored the ectopic expression of galectin-7 in tumours
from non-epithelial origins such as lymphoid or melanomas tumours.
In lymphomas, ectopic expression of galectin-7 was shown to correlate with the metastatic
potential of transplanted lymphomas cell lines [83,85–87]. Further observations in human lymphoid
diseases suggested correlations between tumour progression and accumulation of galectin-7 [86] while
no expression was detected in normal tissues.
Studies were also conducted to investigate the role of galectin-7 in melanoma. Indeed, tissue
analysis on human melanomas and nevi first showed an expression of galectin-7 [88] but in situ
labelling of nevi biopsies suggested that they were mostly the keratinocytes subpopulation of the
biopsies that expressed galectin-7 [60]. In addition, it has been found that when the melanoma cells
B16F1 are injected subcutaneously into mice, galectin-7 can be expressed by the resulting primary
tumour as well as in lung metastasis [60]. However, even if galectin-7 increased the resistance of
melanoma cells to apoptosis, studies on the melanoma cell line B16F1 showed that galectin-7 ectopic
expression did not impact tumour growth and metastasis occurrence when cells are injected into
mice [60].
Contrastingly, one of the major skin cancers apart from melanomas, basal cell carcinoma,
appeared to be devoid of galectin-7 expression [89] while galectin-7 is expressed in normal tissues.
Other carcinomas are also associated with decreased galectin-7 expression such as stomach [90],
urothelial [91,92] and cervix [59] cancer. On the contrary, squamous epithelial and mucous tumours
from head and neck [93], oesophagus [94] and thyroid [95] cancer do express higher galectin-7 levels
than normal tissues.
In breast cancer, the earliest report on galectin-7 being associated to oncogenesis is from a
chemically induced mammary tumour in rat which was found to overexpress galectin-7 contrastingly
to chemically induced colon carcinomas which express a reduced level of galectin-7 [96]. Later
on, galectin-7 was scored among the differentially expressed gene on human breast cancer [97].
Both galectin-3 and galectin-7 were associated with mammary tumour progression with galectin-7
being correlated to pejorative diagnosis when accumulated while reduced galectin-3 was of better
prognosis [98]. Interestingly, these two galectins are mutually exclusive in mammary epithelia with
galectin-7 being a marker of myoepithelial cells and luminal cells being galectin-3 positive [35].
The myoepithelial cells exhibit a basal type phenotype with a proliferative capacity [99,100]. Most
importantly, galectin-7 is overexpressed in basal-like breast tumours [97,101]. Recently, using a
mouse model for ErbB2 mammary tumours, galectin-7 expression was reported to accelerate tumour
progression and the formation of tumour nodules in ErbB2-positive tumours [102]. On the contrary,
using mouse model knocked-out for galectin-3 expression, no correlation was found with breast
tumour progression or metastasis induced by transgenic expression of Mouse Mammary Tumour
Virus- Polyoma Middle T (MMTV-PyMT) oncogene [103].
Furthermore, overexpression of galectin-7 was associated to metastatic potential of various tumour
tissues, notably in breast cancer [101]. In oral squamous cell carcinoma (OSCC), galectin-7 has been
associated with the histological malignancy grading system [104,105]. Consistently, in OSCC cell lines,
galectin-7 downregulation reduces cell migration and invasion whereas its overexpression enhances
cell migration and invasion of cancer cells [52]. Similarly to OSCC, in epithelial ovarian cancer, various
studies described a correlation between galectin-7 ectopic expression in this monostratified epithelia
and overall patient survival [50,106]. In addition, de novo galectin-7 expression was associated with
progression to high-grade tumours and was enriched in metastatic samples compare to low-grade
Int. J. Mol. Sci. 2017, 18, 2760 9 of 17

tumours [50]. On the contrary, in colon cancer, galectin-7 ectopic overexpression prevented metastatic
dissemination [55] and promoted apoptosis after apoptosis induction by stimuli [54].

4.1. Galectin-7 as a Therapeutic Tool

The association of galectins with cancer [29,107] may be related to the well-known alterations
in glycosylation signatures of cancer cells that may have incidental implications on galectins
reactivity [108]. Indeed, during tumour progression, different factors affect protein glycosylation
leading to altered glycan structure and composition as the appearance of truncated glycosylation
motifs or enrichment of polyLacNAc [108–110]. This modification of galectin ligands will necessarily
affect galectin activity and functions and can impact cell growth, adhesion, immunomodulation and
cell migration [109]. As an illustration, modification of the surface glycome regulates galectin-1 binding
to endothelial cells, and more importantly to VEGFR2, thus affecting angiogenesis and response to
anti-VEGF treatments [111]. Among carcinomas, galectins-1 and -3 are the most studied and are
already targeted in clinical trials [107,111,112]. Interestingly, immunomodulating potential is one of the
most powerful actions of these galectins in cancer. Galectin-1 also has a relevant anti-angiogenic
potential [113]. Another relevant function of galectins in cancer biology is cell migration and
particularly adhesion to the MEC and to other cells (including surrounding or endothelial cells) [79].
As a consequence, galectin-7 appeared in the dedicated studies as a potential target for clinical
approaches either as a prognostic marker, a direct modulating protein in cancer or a therapeutic target
for inhibitors.
Indeed, galectin-7 has been proposed to serve as a marker in patients with certain type of cancer.
Interestingly, galectin-7 overexpression on tumour tissues could be correlated to patient survival
notably in ovarian [114] or in cervical [59,115] carcinomas. Furthermore, galectin-7 expression has
been associated with better survival after chemo- or radio-therapies [91,115] and has been proposed to
serve as a predictive marker of chemo- and radio-therapy resistance [116].
Administration of pure recombinant galectin-7 could be efficient in immunosuppressive
approaches targeting T lymphocytes but contrastingly it could enhance invasive potential of tumour
cells [50]. Soluble exogenously added galectin-7 has been used successfully to repair corneal injury in
mice cornea ex vivo [73,74]. In a recent article, St-Pierre and colleagues demonstrated that recombinant
galectin-7 added on tumour cells may rapidly traffic through intracellular compartments including
endocytic vesicle and mitochondria and could induce ectopic expression of galectin-7 [117]. These
new coming results reinforce the rationale of using galectin-7 on tumour that would benefit from its
induced expression, as for example colon cancer [54,55]. On the contrary, using inhibitors of galectin-7
has to be tested in tumours where its expression is associated with pejorative prognosis.
Moreover, development of specific galectin-7 inhibitors that will selectively target the
intracellular or extracellular functions of galectin-7 could be a strategy to inhibit not all but specific
galectin-7-mediated processes [118]. Interestingly, inhibition of the intracellular lectin-activity
of galectin-7 could be easily assessed. As previously demonstrated for galectins-1, -3, -8 and
-9 [119], galectin-7 is able to detect damages to vesicles (Figures 2 and 3). Indeed, addition of a
lysosomal-damaging agent induces intracellular recruitment of galectin-7 to permeabilized lysosomes
indicating that this lectin recognizes altered vesicles (Figure 3). This feature shared by some galectins
allows to identify galectin inhibitors that penetrate the cells and target the CRD domain of a given
galectin, providing a functional assay to assess drug penetration and specificity [120,121]. Hence,
some galectins are efficient to detect damaged vesicular compartment by binding to glycoproteins
abnormally exposed in the cytoplasm due to vesicle integrity failure [119]. This approach is particularly
relevant in the biomedical area where knowing the precise way of action of a chemical compound is
a benefit.
Int.
Int. J.J.Mol.
Mol.Sci.
Sci.2017,
2017,18,
18,2760
2760 10
10 of
of 17
17

Figure 3.
Figure Galectin-7 isis recruited
3. Galectin-7 recruited at
at damaged
damaged lysosomes.
lysosomes. Twelve
Twelve minutes
minutes incubation
incubation with
with the
the
lysosome-damaging agent GPN (glycyl- L -phenylalanine 2-naphthylamide) induces intracellular
lysosome-damaging agent GPN (glycyl-L-phenylalanine 2-naphthylamide) induces intracellular
accumulation of galectin-7 at damaged lysosomes in HaCaT cells. Scale bar = 10 µm.
accumulation of galectin-7 at damaged lysosomes in HaCaT cells. Scale bar = 10 μm.

5. Conclusions
5. Conclusions
Galectin-7 isisaaprototypic
Galectin-7 prototypicgalectin,
galectin,which
whichisispreferentially
preferentiallyfound
foundinin stratified
stratified epithelia
epithelia where
where it
it favours
favours epithelial
epithelial homeostasis.
homeostasis. Though
Though galectin-7-null
galectin-7-null mice
mice or mice
or mice overexpressing
overexpressing galectin-7
galectin-7 in
in the
the epidermis
epidermis are viable
are viable and fertile,
and fertile, they present
they present defective
defective responses
responses to conditions.
to stress stress conditions.
Indeed,Indeed,
acting
acting intra- or extracellularly, galectin-7 participates in diverse processes such
intra- or extracellularly, galectin-7 participates in diverse processes such as the susceptibility as the susceptibilityto
to apoptosis,
apoptosis, cellcell migration
migration and and cell-adhesion.
cell-adhesion. However,
However, the detailed
the detailed mechanism
mechanism of actionof of
action of this
this tissue-
tissue-specific
specific galectingalectin and
and its its partners
partners are mostly
are mostly unknown.
unknown. Thus,
Thus, further
further work
work is isrequired
requiredtotouncover
uncover
galectin-7 functions and ways of action. This is particularly important regarding the
galectin-7 functions and ways of action. This is particularly important regarding the biomedical field biomedical field
because galectin-7
because galectin-7 could
could influence
influence tumour
tumour progression.
progression.Hence,
Hence,specifying
specifyinghow howgalectin-7
galectin-7influences
influencesa
given process could help to design and predict the effects of galectin-7 inhibitors targeting
a given process could help to design and predict the effects of galectin-7 inhibitors targeting diverse diverse
regions of
regions ofthe
theprotein or or
protein generated
generatedrecombinant
recombinantmutant galectin-7
mutant that retain
galectin-7 that only
retain some
onlyof some
the functions
of the
of galectin-7.
functions of galectin-7.
Acknowledgments: This work was supported by FRM (Fondation pour la Recherche Médicale; DCM20121225750)
Acknowledgments: This work was supported by FRM (Fondation pour la Recherche Médicale;
and Fondation ARC (Association pour la Recherche contre le Cancer; PJA 20161204938) grants. We are thankful to
DCM20121225750) and
Juliette Delafosse for Fondation
English ARC (Association pour la Recherche contre le Cancer; PJA 20161204938)
correction.
grants. We are thankful to Juliette Delafosse for English correction.
Conflicts of Interest: The authors declare no conflict of interest.
Conflicts of Interest: The authors declare no conflict of interest.
Abbreviations
Abbreviations
BCR B-Cell Receptor
BCR
CRD B-Cell Receptor Recognition Domain
Carbohydrate
CRD
DMSO Carbohydrate Recognition Domain
Dimethyl Sulfoxide
DMSO
FAF Dimethyl Sulfoxide
F. magna Adhesion Factor
FAF
ECM F. Extracellular
magna Adhesion Factor
Matrix
ECM
HGF Extracellular Matrix
Hepatocyte Growth Factor
HGF
JNK Hepatocyte GrowthKinase
c-Jun N-terminal Factor
JNK
LacNAc c-Jun N-terminal Kinase
N-Acetyl-Lactosamine
LacNAc
MMP N-Acetyl-Lactosamine
Matrix Metalloproteinase
MMP
MMTV-PyMT Matrix
MouseMetalloproteinase
Mammary Tumor Virus – Polyoma Middle T
MMTV-PyMT Mouse Mammary Tumor Virus – Polyoma Middle T
NES Nuclear Export Signal
NES Nuclear Export Signal
NF-κB Nuclear Factor kappa B
NF-κB Nuclear Factor kappa B
NLS Nuclear Localisation Signal
NLS Nuclear Localisation Signal
OSCC Oral Squamous Cell Carcinoma
OSCC Oral Squamous Cell Carcinoma
Int. J. Mol. Sci. 2017, 18, 2760 11 of 17

SV-40 Simian Virus-40

TGFβ Transforming Growth Factor β
UVB Ultraviolet B
WT Wild Type

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