RUNX3 protein is overexpressed in human basal cell carcinomas.
ABSTRACT Basal cell carcinomas (BCC), which are the most common form of skin malignancy, are invariably associated with the deregulation of the Sonic Hedgehog (Shh) signalling pathway. As such, BCC represent a unique model for the study of interactions of the Shh pathway with other genes and pathways. We constructed a tissue microarray (TMA) of 75 paired BCC and normal skin and analysed the expression of beta-catenin and RUNX3, nuclear effectors of the wingless-Int (Wnt) and bone morphogenetic protein/transforming growth factor-beta pathways, respectively. In line with previous reports, we observed varying subcellular expression pattern of beta-catenin in BCC, with 31 cases (41%) showing nuclear accumulation. In contrast, all the BCC cases tested by the TMA showed RUNX3 protein uniformly overexpressed in the nuclei of the cancer cells. Analysis by Western blotting and DNA sequencing indicates that the overexpressed protein is normal and full-length, containing no mutation in the coding region, implicating RUNX3 as an oncogene in certain human cancers. Our results indicate that although the deregulation of Wnt signalling could contribute to the pathogenesis of a subset of BCC, RUNX3 appears to be a universal downstream mediator of a constitutively active Shh pathway in BCC.
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ABSTRACT: The skin and its appendages constitute the largest organ of the body. Its stratified epithelia offer protection from environmental stresses such as dehydration, irradiation, mechanical trauma, and pathogenic infection, whereas its appendages, like hair and sebaceous glands, help regulate body temperature as well as influence animal interaction and social behavior through camouflage and sexual signaling. To respond to and function effectively in a dynamic external environment, the skin and its appendages possess a remarkable ability to regenerate in a carefully controlled fashion. When this finely tuned homeostatic process is disrupted, skin diseases such as cancers may result. At present, the molecular signals that orchestrate cell proliferation, differentiation, and patterning in the skin remain incompletely understood. It is increasingly apparent that many morphogenetic pathways with key roles in development are also important in regulating skin biology. Of these, Wnt signaling has emerged as the dominant pathway controlling the patterning of skin and influencing the decisions of embryonic and adult stem cells to adopt the various cell lineages of the skin and its appendages, as well as subsequently controlling the function of differentiated skin cells. Here we will review established concepts and present recent advances in our understanding of the diverse roles that Wnt signaling plays in skin development, homeostasis, and disease.Cold Spring Harbor perspectives in biology 12/2012; · 9.63 Impact Factor
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ABSTRACT: The aim of this study is to investigate the possible roles of runt-related transcription factor 3 (RUNX3) and β-catenin in the carcinogenesis of sporadic colorectal tubular adenomas. The expression of the RUNX3 and β-catenin proteins was evaluated by immunohistochemistry in 23 normal colorectal mucosa (NCM), 81 sporadic colorectal tubular adenomas with different dysplasias (SCTA-D) (mild n = 33, moderate n = 23, and severe n = 25 dysplasia), and 48 sporadic colorectal tubular adenomas with cancerous changes (SCTA-Ca). RUNX3 methylation was assessed by methylation-specific polymerase chain reaction (MSP), combined with laser capture microdissection (LCM), in 17 NCM, 41 SCTA-D (mild n = 15, moderate n = 12, and severe n = 14 dysplasia), and 17 SCTA-Ca tissues. Compared to NCM (82.6 %), RUNX3 in SCTA-D (54.3 %) and SCTA-Ca (27.1 %) was significantly downregulated (P < 0.05). In NCM, SCTA-D, and SCTA-Ca, the incidence of positive expression for β-catenin was 13.0, 60.5, and 79.2 %, respectively. A statistically significant difference was observed (P < 0.05). RUNX3 levels were markedly higher in adenoma with mild dysplasia (75.8 %) and moderate dysplasia (60.9 %) than in adenoma with severe dysplasia (20.0 %) (both with P < 0.05). Likewise, the expression of β-catenin in severe dysplasia adenoma was 84.0 %, which was significantly higher than that in mild dysplasia adenoma (39.4 %). An inverse correlation was found between the protein expression of RUNX3 and β-catenin in SCTA-D and SCTA-Ca (P < 0.05). MSP results showed that RUNX3 methylation in NCM, SCTA-D, and SCTA-Ca was 5.9, 17.1, and 41.2 %, respectively, with a statistically significant difference between NCM and SCTA-Ca (P < 0.05). However, no significant difference of RUNX3 methylation was observed among different dysplasia groups. RUNX3 and β-catenin play important roles in the carcinogenesis of sporadic colorectal tubular adenomas. In addition, hypermethylation of RUNX3 can downregulate its expression.Tumor Biology 03/2014; · 2.52 Impact Factor
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ABSTRACT: Transcription factors of the RUNX family (RUNXs), which play pivotal roles in normal development and neoplasia, are regulated by various post-translational modifications. To understand the molecular mechanisms underlying the regulation of RUNXs, we performed a large-scale functional genetic screen of a fly mutant library. The screen identified dPias (the fly ortholog of mammalian PIASs), an E3 ligase for the SUMO (small ubiquitin-like modifier) modification, as a novel genetic modifier of lz (the fly ortholog of mammalian RUNX3). Molecular biological analysis revealed that lz/RUNXs are sumoylated by dPias/PIAS1 at an evolutionarily conserved lysine residue (K372 of lz, K144 of RUNX1, K181 of RUNX2 and K148 of RUNX3). PIAS1-mediated sumoylation inhibited RUNX3 transactivation activity, and this modification was promoted by the AKT1 kinase. Importantly, PIAS1 failed to sumoylate some RUNX1 mutants associated with breast cancer. In nude mice, tumorigenicity was promoted by RUNX3 bearing a mutation in the sumoylation site, but suppressed by wild-type RUNX3. Our results suggest that RUNXs are sumoylated by PIAS1, and that this modification could play a critical role in the regulation of the tumor-suppressive activity of these proteins.Oncogenesis. 01/2014; 3:e101.
RUNX3 protein is overexpressed in human basal cell carcinomas
M Salto-Tellez1,2,5, BK Peh2,5, K Ito2,4, SH Tan3, PY Chong1,2, HC Han2, K Tada2, WY Ong3,
R Soong1,2, DC Voon4and Y Ito2,4
1Department of Pathology, National University Hospital, Yong Loo Lin Medical School, National University of Singapore (NUS),
Singapore, Singapore;2Oncology Research Institute, National University of Singapore (NUS), Singapore, Singapore;3National Skin
Centre, Singapore, Singapore and4Institute of Molecular and Cell Biology, Singapore, Singapore
Basal cell carcinomas (BCC), which are the most common
form of skin malignancy, are invariably associated with
the deregulation of the Sonic Hedgehog (Shh) signalling
pathway. As such, BCC represent a unique model for the
study of interactions of the Shh pathway with other genes
and pathways. We constructed a tissue microarray (TMA)
of 75 paired BCC and normal skin and analysed the
expression of b-catenin and RUNX3, nuclear effectors of
the wingless-Int (Wnt) and bone morphogenetic protein/
transforming growth factor-b pathways, respectively. In
line with previous reports, we observed varying subcellular
expression pattern of b-catenin in BCC, with 31 cases
(41%) showing nuclear accumulation. In contrast, all the
BCC cases tested by the TMA showed RUNX3 protein
uniformly overexpressed in the nuclei of the cancer cells.
Analysis by Western blotting and DNA sequencing
indicates that the overexpressed protein is normal and
full-length, containing no mutation in the coding region,
implicating RUNX3 as an oncogene in certain human
cancers. Our results indicate that although the deregula-
tion of Wnt signalling could contribute to the pathogenesis
of a subset of BCC, RUNX3 appears to be a universal
downstream mediator of a constitutively active Shh
pathway in BCC.
Oncogene (2006) 25, 7646–7649. doi:10.1038/sj.onc.1209739;
published online 12 June 2006
Keywords: basal cell carcinoma; RUNX3; b-catenin;
Cutaneous basal cell carcinomas (BCC) comprise
approximately 80% of non-melanoma skin cancers
and have been reported as the most common human
malignancy in the United States (Rubin et al., 2005).
The molecular pathogenesis of BCC bears the distinc-
tion of being almost entirely associated to the deregula-
tion of the Sonic Hedgehog (Shh) signalling pathway
(for a recent review on this topic, see Daya-Grosjean
and Couve-Privat, 2005). Originally identified as a
determinant of segment polarity in Drosophila, Shh is
a secreted glycoprotein that plays a major role in
vertebrate development. The binding of Shh to its
receptor, the 12-pass transmembrane protein patched
homologue 1 (PTCH1), relieves the suppression of
another transmembrane protein, the G-protein-coupled
receptor, smoothened (SMO). SMO in turn initiates a
signalling cascade that leads to the activation of the Ci-
like (GLI) family of transcription factors, which are the
primary effectors of the Shh signal. Mutations in Shh,
PTCH1, SMO and GLI have all been identified in BCC
cases, with loss-of-function mutation in PTCH1 identi-
fied in 100 and 12–38% of familial and sporadic BCC
cases, respectively (Dahmane et al., 1997; Unden et al.,
1997; Daya-Grosjean and Couve-Privat, 2005).
Similar to the Shh pathway, the wingless-Int (Wnt)
and bone morphogenetic protein/transforming growth
factor-b (BMP/TGF-b) pathways play central develop-
mental roles that are conserved from the fruitfly to
human (Chen and Meng, 2004; Logan and Nusse, 2004).
Mutations and deregulation of the Wnt pathway are the
characteristic features of many human cancers, most
notably in intestinal malignancies (Gregorieff and
Clevers, 2005). Several lines of evidence hint at a role
for the Wnt pathway in BCC. Firstly, the Wnt pathway
is involved in hair follicle morphogenesis and its ligands
are known targets of Shh signalling (Reddy et al., 2001;
Andl et al., 2002). Secondly, the Wnt pathway has been
linked to other skin malignancies: 75% of human
pilomatricomas cases bear activating mutations of b-
catenin (Chan et al., 1999), and the deregulation of Wnt
pathway is linked to the progression of human
melanomas (Rubinfeld et al., 1997; Weeraratna, 2005).
For these reasons, the involvement of Wnt signalling in
BCC pathogenesis has been keenly evaluated. Specifi-
cally, efforts have been focused on the incidence of
nuclear accumulation of b-catenin, a hallmark of
constitutive activation of Wnt signalling, in BCC tumor
samples (Behrens et al., 1996; Huber et al., 1996).
However, several such attempts to detect nuclear
accumulation of b-catenin have yielded conflicting
observations (Boonchai et al., 2000; Yamazaki et al.,
2001; El-Bahrawy et al., 2003; Saldanha et al., 2004). To
further verify the involvement of Wnt pathway in BCC,
we constructed a tissue microarray (TMA) of 75 BCC
tumors and corresponding normal skin samples, and
analysed these samples for b-catenin expression and
Received 31 March 2006; accepted 8 May 2006; published online 12 June
Correspondence: Professor Y Ito, Institute of Molecular and Cell
Biology, 61 Biopolis Drive – Proteos, Singapore 138673, Singapore.
5These authors contributed equally to this work.
Oncogene (2006) 25, 7646–7649
& 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00
subcellular localization. Our study detected nuclear
accumulation of b-catenin in 31 of 75 (41%) BCC
tumor samples. Whereas the expression of b-catenin is
uniformly restricted to the cell membrane in normal
epidermis (Figure 1a and b), its expression varied
considerably between BCC samples. Expression ranged
from being undetectable (Figure 1c) to predominant
expression in the nucleus (Figure 1d), cytoplasm
(Figure 1e) or cytoplasm and membrane (Figure 1f).
In certain cases, combined expression in the cytoplasm
and nucleus, or membrane was observed (Figure 1d and
f, respectively). Together, these observations suggest
that activation of Wnt signalling is evident in a subset of
BCC, but the subcellular localization of b-catenin varies
significantly between tumor samples.
In a previous study, Boonchai et al. (2000) reported
that nuclear b-catenin was undetectable in all 195 cases
of BCC analysed. However, several subsequent studies
using different antibodies were able to detect nuclear b-
catenin in 23–70% of BCC samples (Yamazaki et al.,
2001; El-Bahrawy et al., 2003; Saldanha et al., 2004).
Although the precise reasons for such discrepancies is
not clear, it has been suggested that this could be caused
by differences in tissue fixation and processing (Yama-
zaki et al., 2001; Saldanha et al., 2004). Our findings are
consistent with the latter reports and serve to validate the
effectiveness and robustness of our TMA methodology.
In addition to Wnt ligands, Shh is also known to
upregulate ligands of the BMP pathway, specifically
BMP4 and BMP7 (Kawai and Sugiura, 2001; Gianako-
poulos and Skerjanc, 2005). To investigate the involve-
ment of this pathway in BCC, we studied the expression
profile of RUNX3, a nuclear effector of the BMP/TGF-
b pathways, and a key tumor suppressor gene in the
gastric epithelium (Li et al., 2002; Ito and Miyazono,
2003; Bae and Choi, 2004). The runt-related (RUNX)
family of transcription factors share homology with the
Drosophila segmentation gene runt and encode the
DNA-binding subunit of the heterodimeric transcrip-
tion factor polyomavirus enhancer binding protein 2/
core-binding factor complex (PEBP2/CBF) (for classifi-
cation and nomenclature, see van Wijnen et al., 2004).
RUNX1 is critical for the generation and maintenance
of hematopoietic stem cells and is frequently targeted by
chromosomal translocations and point mutations in
human leukemia. Although RUNX2 is yet to be directly
associated with human tumors, its oncogenicity has been
demonstrated in mouse models, in cooperation with
ectopically expressed c-myc (Blyth et al., 2005). RUNX3
was initially described as a candidate tumor suppressor
in the gastric epithelium and is epigenetically silenced in
greater than 50% of gastric cancer cell lines (Li et al.,
2002). More recently, we have demonstrated that
RUNX3 is not detectable in 43 of 97 (44%) cases of
gastric cancer, and a further 38% showed mislocaliza-
tion in the cytoplasm, therefore suggesting that RUNX3
is inactivated in >80% of gastric cancers (Ito et al.,
2005). Reduced expression of RUNX3 has now been
observed in numerous human malignancies, including
bladder (Kim et al., 2005), liver (Mori et al., 2005),
colorectal (Ku et al., 2004) and lung cancers (Yanada
et al., 2005). Furthermore, RUNX3 point mutations
have been discovered in human gastric and bladder
cancers (Li et al., 2002; Kim et al., 2005).
Immunohistochemical staining of our TMA samples
showed that RUNX3 protein is expressed in normal skin
(Figure 2a), with distinct nuclear, mild-to-moderate
positivity (grade 1–2) in approximately 75% of epider-
mal cells (Figure 2b). The expression is present in all the
epidermal layers. The number of RUNX3-expressing
cells is particularly prominent in the basal cell layer, but
patchy in the prickle cell, granular cell and keratin
layers. The expression is also prominent in the hair
shaft, being more prominent in the outer root sheath of
the pilosebaceous unit and the associated eccrine sweat
glands (data not shown). The analysis of BCC samples
showed that there is a strong, uniform (grade 3) nuclear
expression of the RUNX3 in all 75 cases (Figure 2c and
d). The expression was present in virtually 100% of the
BCC neoplastic cell, irrespective of the histological
subtype. Furthermore, expression of RUNX3 within the
well-demarcated ‘islets’ of neoplastic cells is distinctly
higher than that of the adjacent normal epidermal
BCC samples. Construction of TMA was performed as described
by Salto-Tellez et al. (2004) with minor modifications. Immuno-
histochemistry staining by anti-b-catenin mouse monoclonal anti-
body (BD Transduction Laboratories, Lexington, KY, USA, clone
14) was performed following published methods (Saldanha et al.,
2004). (a) Hematoxylin–eosin stain (H&E) on normal epidermis;
(b) corresponding b-catenin stain with characteristic membranous
positivity; (c–f) b-catenin expression in BCC (see text for details).
Immunohistochemistry for b-catenin on normal and
RUNX3 overexpression in BCC
M Salto-Tellez et al
tissue. Taken together, RUNX3 appears overexpressed
in BCC compared to the expression levels observed in
We next sought to investigate the nature of the
RUNX3 proteins expressed in BCC. Firstly, we
performed Western blot analysis on normal skin
(ATCC-CRL-7761) and BCC-derived (ATCC-CRL-
7762) cell lines, using a RUNX3-specific monoclonal
antibody R3-5G4 (Ito et al., 2005). Figure 3 shows that
the RUNX3 proteins expressed in CRL-7762 cells are of
the same length as that of ectopically expressed, full-
length RUNX3 in transfected COS7 cells, suggesting
that functional RUNX3 is expressed in BCC cells.
Importantly, RUNX3 expression is markedly stronger
in CRL-7762 compared to the normal CRL-7761,
confirming the observation of RUNX3 overexpression
in BCC TMA samples. Two RUNX3-related bands
were detected in CRL-7762 and SNU5 cell lysates,
which may represent different RUNX3 isoforms,
although the doublet could also be caused by phos-
To provide direct evidence that the RUNX3 proteins
overexpressed in BCC are full-length and intact, we
analysed the RUNX3 gene for point mutations. The
entire RUNX3-coding region of CRL-7761 (normal),
CRL-7762 (BCC-derived) and selected BCC tumors was
sequenced. However, these analyses showed no evidence
of mutation in the RUNX3-coding region. Therefore,
our data indicate that the overexpressed RUNX3 in
BCC is without structural alteration or mutation, and
Although it is well established that deregulation of the
Shh pathway plays a central role in the molecular
pathogenesis of BCC, the specific targets and mechan-
isms through which tumorigenesis is effected remain
elusive. Of equal interest is the potential involvement of
other, well-characterized pathways, implicated in other
human cancers, that cooperate with the breakdown in
Shh signalling. A significant player appears to be the
tumor suppressor gene p53, which is mutated in
approximately 50% of sporadic BCC (Ziegler et al.,
1993). Our data show that, in line with previous studies,
b-catenin is targeted to the nucleus in some BCC
samples. However, the frequency at which this occurs
indicates that although Wnt signalling is involved in the
progression of some BCC, it is not likely to be a primary
mechanism by which the Shh signal is mediated. In
contrast, overexpression of RUNX3 in the nucleus of
neoplastic cells is observed in all of the 75 samples in our
TMA, therefore strongly implicating a role for RUNX3
as an oncogene downstream of the Shh pathway. This
striking observation is made all the more significant in
view of the current understanding of RUNX3 as a
tumor suppressor in several human malignancies, most
notably in gastric cancer. Moreover, RUNX3 is also a
downstream target of the TGF-b tumor suppressor
pathway. Although all members of the RUNX family,
most notably RUNX2, are known to promote tumor-
igenecity in mouse models (Cameron and Neil, 2004;
Yanagida et al., 2005), our study implicates RUNX3
acting as a putative oncogene in human cancer.
An important implication of our findings is the
possibility of cooperation between the Shh pathway
and BMP/TGF-b pathways in BCC, which warrants a
thorough investigation. It is well established that the
Shh pathway is modulated via a negative feedback loop
through PTCH1, as PTCH1 itself is a positive target of
GLI3 (Goodrich et al., 1996; Marigo and Tabin, 1996).
In BCC, this intrinsic circuitry control is broken and
although the genetics may differ, they invariably lead to
the constitutive activation of the Shh pathway. Im-
portantly, in addition to PTCH1, GLI transcription
factors are also known to transcriptionally regulate
several of the BMPs (Kawai and Sugiura, 2001;
extracts from COS-7 cells expressing exogenous RUNX3; normal
skin cell line CRL-7761 (American Type Culture Collection
(ATCC), Manassas, VA, USA); BCC-derived cell line CRL-7762
(ATCC); and gastric cancer line SNU5 (ATCC), which over-
expresses endogenous RUNX3. Western blot was performed using
RUNX3-specific monoclonal antibody R3-5G4, as described by Ito
et al. (2005).
Western blot analysis of RUNX3 expression. Whole-cell
on tissue samples. The procedure for immunohistochemical
staining with anti-RUNX3 monoclonal antibody R3-6E9 was the
same as that described by Ito et al. (2005). (a) H&E stain on normal
epidermis; (b) corresponding RUNX3 expression in normal
epidermis; (c) low-power view of a TMA punch including normal
epidermis and BCC in the dermis; (d) high-power view showing a
rim on normal epidermis (top) and the nodules of infiltrating BCC
with strong, nuclear antibody expression.
Immunohistochemical detection of RUNX3 expression
RUNX3 overexpression in BCC
M Salto-Tellez et al
Gianakopoulos and Skerjanc, 2005). Whether this then
leads to the nuclear accumulation and overexpression of
RUNX3 in BCC must now be a subject for rigorous
examination. If substantiated, then understanding the
involvement of RUNX3 in BCC will avail a new avenue
of unraveling the complex pathogenesis of this highly
This work was supported by the Agency for Science,
Technology and Research (A*STAR), Singapore. M Salto-
Tellez and SH Tan are recipients of Singapore Cancer
Syndicate Grants MN005 and BS002, Agency for Science,
Technology and Research, Singapore.
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RUNX3 overexpression in BCC
M Salto-Tellez et al