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2 in Colorectal Carcinomas Is Regulated by ß-Catenin1
Department of Pathology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany
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ABSTRACT |
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2 chain of laminin-5, one of the best known invasion markers, is strongly overexpressed in disseminating and infiltrating tumor cells at the invasive front of colorectal carcinomas. The same tumor cells show nuclear accumulation of the oncoprotein ß-catenin, which together with T-cell factor-DNA-binding proteins, functions as transcriptional activator of genes involved in tumor progression. Here we show that ß-catenin activates the human laminin-5 2 gene through two T-cell factor-binding elements in a synergistic manner together with hepatocyte growth factor and conclude that laminin-5 2 is another important target gene of nuclear ß-catenin during tumor progression. |
Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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A major component of the BM are laminins, heterotrimeric molecules consisting of three variable subunits (
-, ß-, and -chains). Laminin-5, built up by the chains 3, ß3, and 2, is expressed in the BM of intestinal mucosa (3)
, is an adhesion substrate for the epithelial cells, and regulates epithelial cell migration during epithelial regeneration and repair processes (4)
. Increasing numbers of studies demonstrated a link between laminin-5 overexpression and the invasive activity of carcinoma cells (5)
. Thereby the 2 chain of laminin-5, cleaved by matrix-metalloproteases, seems to be an important activator of tumor cell migration (6)
. Pyke et al. (7)
and Sordat et al. (8)
found an abnormal strong expression of the laminin-5 2 chain in dedifferentiated cells of colon carcinomas dissociating from the neoplastic tubules, demonstrating that laminin-5 2 is one of the most specific invasion markers (9)
. We described a nuclear accumulation of ß-catenin predominantly in the same dedifferentiated, mesenchyme-like tumor cells found at the invasive front of colorectal carcinomas, whereas tumor cells in central, differentiated areas often retain membranous and cytoplasmic expression and lack nuclear ß-catenin (10
, 11)
. Overexpression of ß-catenin is found in most colorectal carcinomas because of loss-of-function mutations in the APC tumor suppressor gene, the initial genetic alteration in 
80% of these tumors. As an effector of the WNT-signaling pathway, nuclear ß-catenin is able to bind to the TCF-family of DNA-binding proteins (e.g., TCF-4), and both molecules together function as a transcriptional activator. Accordingly, ß-catenin can accumulate in the nuclear TCF-bound fraction and lead to a constitutive target gene activation in colorectal cancer cells with mutated APC (12)
. Recently defined ß-catenin target genes necessary for invasive growth, like matrilysin (13
, 14)
, CD44 (15)
, and uPAR (16)
, support a direct role of nuclear ß-catenin in malignant tumor progression. Thus, the distinct intracellular distribution of ß-catenin within the tumors, probably regulated by still unspecified environmental signals, has a strong impact on this process.
It is not clear how overexpression of the important invasion factor laminin-5 is activated selectively in dissociating and invading cells of colon carcinomas. A migration-related element was narrowed down to nucleotides -613 and +55 in the promoter of the human LAMC2 (17)
. Olsen et al. (18)
showed that the stimulatory effect of HGF/scatter factor is mediated through activation of the transcription factor JunD binding to two AP-1 sites in the LAMC2 promoter. Three facts prompted us to investigate a potential role of nuclear ß-catenin as an additional regulator of the laminin-5 2 chain expression: (a) both laminin 2 and nuclear ß-catenin are overexpressed in dedifferentiated tumor cells at the invasive site of colorectal cancers; (b) nuclear ß-catenin together with TCF-4 acts as an transcriptional regulator; and (c) nuclear ß-catenin was already shown as a transcriptional activator of other genes involved in tumor invasion and malignant progression.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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Immunohistochemistry.
Immunohistochemistry was performed as described (11)
. A polyclonal rabbit anti-ß-catenin antiserum (1:750; Sigma Chemical Co., Deisenhofen, Germany) and mouse monoclonal antibody against laminin 2 (1:50; clone D4B5; Chemicon) was used in this study.
In Situ Hybridization.
The mRNA riboprobe method was performed as described (19)
with -[35S]UTP-labeled probes. Briefly, the complete 4.4-kb cDNA for human laminin 2 (kindly provided by Sirpor Salo, Department of Biochemistry, Univeristy of Oulu, Oulu, Finland) was subcloned in pCIneo (Promega, Mannheim, Germany). In vitro transcription with T3 RNA polymerase after XhoI digestion was used for generation of the specific antisense riboprobe and with T7 RNA-polymerase after NotI digestion for the sense-control riboprobe. Formalin-fixed, paraffin-embedded sections were deparaffinized, digested 10 min with Pronase (200 µg/ml), postfixed for 5 min in 4% paraformaldehyde, and acetylated for 10 min in 0.25% acetic anhydride. Each section was hybridized with 3 x 106 cpm-labeled probe in 50 µl hybridization buffer [50% formamide, 10% dextrane sulfate, 0.2 mg/ml tRNA, 2 x SSC, 10 mM Tris-HCl (pH 7.5), 0.5 mM EDTA (pH 8.0), and 10 mM NaH2 PO4 (pH 6.0) in diethyl pyrocarbonate-treated water] for 16 h at 48°C. The sections were washed at 40°C in 2 x SSC/0.5% ß-mercaptoethanol and at 40°C in 0.5 x SSC/0.5% ß-mercaptoethanol treated with RNase A (20 µg/ml) for 15 min at 37°C and washed again in 2 x SSC/0.5% ß-mercaptoethanol for 2 h at 40°C. After dehydration autoradiography was performed (Kodak NTB-2 nuclear track emulsion) for 1–4 weeks, and sections were counterstained in hemalaun.
Electromobility Shift Assays.
The following oligonucleotides (double-stranded) were used as probes or for competition: lam 1.TCF: 5'-TTG TCT TCC TTG ATG TCC TTT; lam 1.TCF (mut): 5'-TTG TCT TCC TAG GCG TCC TTT; lam 2.TCF: 5'-ACC ACC TGA TCA AGG AAA AGG; lam 2.TCF (mut): 5'-ACC ACC TGG CCT AGG AAA AGG; x: 5'-CCT CCC AGT TTG AGG AAG GGG; and myc: 5'-CGC ACC TTT GAT TTC TGC ACC TTT GAT TTC T. Probes were end labeled to 3 x 108 dpm/µg. Probe (0.5 ng) was incubated with 0.5 µg of bacterially expressed GST-TCF-4(DNA-binding-domain; codons 265–496) or GST alone as described (14)
.
DNA Clones.
A lacZ reporter clone driven by the promoter (-613 to +55) of the human laminin 2 gene (pHH2) was a gift from Sirpor Salo and Karl Tryggvason (Oulu, Finland; Ref. 17
). For sequential mutation of both TCF-sites in pHH2 (pHH-2 mut1.2.TCF) with the Quick Change kit (Stratagene, Heidelberg, Germany) we used the following primers (and corresponding antisense primers): TCFmut, 5'-CGA CTG ACT TGT CTT CCT AGG CGT CCT TTA AGC CGG AGC; and TCFmut, 5'-CGA TAA AAC CAC CTG GCC TAG GAA AAG GAA GGC ACA GC. Plasmids provided by other researchers: pGST-TCF4(DBD), pcDNA/hTCF4, and pcDNA/DN-TCF4 from Bert Vogelstein (Johns Hopkins University, Baltimore, MD); pcDNAhß-catenin from Hans Clevers (University Medical Center, Utrecht, Netherlands); and pRSVjunD from Edgar Serfling (University of Würzburg, Würzburg, Germany).
Transfections and Reporter Assays.
Transfections and reporter assays of 293T and SW480 cells (American Type Culture Collection, Manassas, VA) with indicated expression vectors (pcDNA/hTCF4, pcDNA/DN-TCF4, pcDNAhß-catenin, and pRSVjunD) or empty background vectors were done as described (14)
. When indicated, HGF (50 ng/ml final concentration) was added 20 h after transfection. Cells were harvested 40 h after transfection. LacZ activity was normalized with luciferase activity of cotransfected pCMVluc for control of transfection efficiency. Experiments were done at least three times.
Confocal Laser Scanning Microscopy and Immunoblots.
SW480 cells were grown at low or high density on 10-mm glass coverslips in six-well culture plates. Staining against ß-catenin antiserum and E-cadherin and subsequent confocal laser scanning microscopy were performed as described directly on the removed coverslips (20)
. Immunoblots were performed using modified standard protocols. In brief, whole cell extracts were made of the remaining cells in 1 ml lysis buffer [2% SDS, 100 mM DTT, 0.2 mM phenylmethylsulfonyl fluoride, and 60 mM Tris-HCl (pH 6.8)]. Extracts (10 µg/lane) were separated on a 10% SDS-polyacrylamide gel, blotted on nitrocellulose, and incubated with the indicated primary antibodies diluted in blocking buffer (5% nonfat dry milk, 0.5% Tween 20; mouse anti c-myc, 1:200, clone 9E11; Novocastra, Newcastle, United Kingdom), mouse anti-ß-actin (1:1000, clone AC-15; Sigma Chemical Co., St. Louis, MO), laminin 2, and E-cadherin (as described above) for 1 h at room temperature. After washing and incubation with peroxidase-coupled species-specific secondary antibodies, the signal was developed using Super Signal (Pierce, Bonn, Germany) according to manufacturer’s protocol.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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2 and Nuclear ß-Catenin at the Invasive Front of Colorectal Carcinomas.2 chain and nuclear ß-catenin in dedifferentiated invading tumor cells. In contrast more differentiated tumor cells in central tumor areas, characterized by a lack of nuclear ß-catenin, did not express laminin 2 (Fig. 1, A–D)
. The correlated expression of both proteins and the fact that laminin 2 is up-regulated at mRNA level as demonstrated by in situ hybridization (Fig. 1, E–H)
led to our hypothesis that the laminin 2 chain gene is another target gene of the transcriptional regulator TCF-4/ß-catenin in invading tumor cells.
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2 Promoter through Two TCF-binding Sites.
. Using electromobility shift assays we could demonstrate a specific binding of TCF-4 to the two elements (lam 1.TCF, nt -436 to -428; lam 2.TCF, nt -20 to -12; Fig. 2B
).
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. In 293T epithelial cells overexpression of TCF4 (x2.4) or ß-catenin (x1.8) alone had only a weak effect on the promoter. Coexpression of both proteins led to a significant (x6.1) activation. However, because this effect was not very strong we tested a combination with the already described activators JunD and HGF. JunD (x2.8) and HGF (x1.6) alone or in combination (x3.8) had only weak stimulatory function. However, coexpression of TCF-4/ß- catenin had a strong effect on JunD (x32.1), HGF (x14.3), and JunD/HGF (x48.2), which indicates synergistic function of all of the described elements of the human LAMC2 promoter. To additionally demonstrate functional relevance, the same point mutations, which where shown to abolish TCF-4 binding to both elements (Fig. 2)
, were introduced in the LAMC2 reporter construct (pHH-2 mut1.2.TCF). The stimulation by TCF-4/ß-catenin of this construct was reduced to 
50% of the wild-type promoter (Fig. 3B)
. However, the remaining activity indicates a still existing direct or indirect effect of ß-catenin on the promoter. Therefore, we again screened the promoter sequence for potential TCF binding not fitting perfectly with the known consensus sequences. However, the only similar sequence found (termed x, nt -357 to -350) did not bind TCF-4 (Fig. 2, A and B
, Lane 20). As expected the weak activation by HGF was similar in both wild-type and mutated promoter constructs.
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. Moreover the mutated reporter construct, abolishing binding of TCF-4 to the two defined elements, was less active in SW480. Again the remaining, albeit weaker inhibition by dnTCF-4 of the mutated reporter indicates additional effects of TCF/ß-catenin (see "Discussion").
Effect of Nuclear ß-Catenin on Endogenous Laminin 2 Expression.
We have demonstrated previously that depending on cell density, SW480 cells can undergo differentiation from mesenchyme-like, fibroblastoid cells characterized by nuclear ß-catenin and cytoplasmic E-cadherin toward an epithelial phenotype indicated by retranslocation of ß-catenin and E-cadherin to the cellular membrane (20)
. We used this cellular model, which mimics the phenotypical switch processes detectable between central and invasive areas of colon carcinomas, to investigate the role of nuclear ß-catenin on endogenous laminin 2 expression. SW480 were either grown at low density in a fibroblastoid form (high amounts of nuclear ß-catenin) or at high density with epithelial phenotype (lack of nuclear ß-catenin; Fig. 4A
). Immunoblots using extracts of these cells demonstrated a reduced expression of laminin 2 chain in SW480 lacking nuclear ß-catenin (Fig. 4B)
. As control we analyzed expression of c-myc, the first described ß-catenin target gene (21)
, which was also reduced in the same extracts, whereas the expression levels of the control proteins ß-actin and E-cadherin remained unaffected by the level of nuclear ß-catenin.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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2 chain of laminin-5 in dedifferentiated tumor cells at the invasive front of colorectal carcinomas. On the basis of this observation we showed that TCF-4/ß-catenin can: (a) activate the promoter of LAMC2 through two TCF binding sites; and (b) increase the stimulatory effect of HGF and JunD on LAMC2 transcription in epithelial cells in a synergistic manner. The expression of endogenous laminin 2 correlated with the amounts of nuclear ß-catenin in these cells. Furthermore, dnTCF suppressed the activity of the LAMC2 promoter and mutations of both TCF-sites in the LAMC2 promoter reduced the activity and stimulation by TCF/ß-catenin; however, the mutated construct was not completely resistant. This could be attributable to cryptic TCF-binding sites, which were not detected. Alternatively, ß-catenin could directly activate at other promoter elements. Most likely it is an indirect effect, because ß-catenin was also shown to activate transcription of the c-jun and fra-1 genes (16)
, which then could exert a stimulatory effect at the two described AP-1 sites in the LAMC2 promoter. On the basis of our data we conclude that LAMC2 is a target gene of the oncoprotein ß-catenin during the invasive process of colorectal carcinomas.
Laminin-5 stimulates migration of epithelial cells. Salo et al. (17)
narrowed down a migration active element in the LAMC2 gene between -613 and +55 and additionally described that basic epithelial expression is regulated outside this region. Olsen et al. (18)
showed that HGF activation of LAMC2 is mediated through binding of JunD to two AP-1 elements within 100 bp upstream of the transcriptional start site, the region where we defined the second TCF-binding site. TCF-family proteins are known to induce strong conformational changes on promoters by bending the DNA. Moreover TCF can either bind the transcriptional repressor groucho or the activator ß-catenin (18)
. Binding of the coactivators p300/CBP to TCF/ß-catenin is thought to alter the chromatin structure thereby making the promoter accessible to other transcription factors (22)
. These data could explain our observation of a much stronger LAMC2 promoter stimulation by HGF and/or JunD in cooperation with TCF-4/ß-catenin. Thus, the observed nuclear overexpression of ß-catenin particularly in dedifferentiated tumor cells at the invasive front could be a prerequisite and support other factors to induce the strong expression of laminin 2 detectable in these cells.
An increasing number of identified ß-catenin target genes like MMP-7 (13
, 14)
, CD44 (15)
, and uPAR (16)
are directly involved in the process of tumor invasion and dissemination. The fact that laminin-5 is one of the best invasion markers and that uPAR and laminin-5 are coexpressed in tumor cells (9)
support our data that laminin-5 2 chain is another target of ß-catenin. Thus, nuclear ß-catenin might activate a cluster of target genes leading to a phenotypic switch toward dedifferentiated, mesenchyme-like tumor cells at the invasive front, which is necessary for tumor progression. Recently we described that nuclear accumulation of ß-catenin in tumor cells at the invasive front can only be transient because tumor cells in growing metastases show again a differentiated phenotype lacking nuclear ß-catenin (20)
and again a reduced expression of laminin 2 (not shown). This indicates that exogenic signals from the specific tumor environment, particularly the extracellular matrix, regulate the intracellular distribution of ß-catenin and consequently activation of its target genes. Accordingly, Sordat et al. (23)
described that also the expression level of laminin-5 in a mouse model depends on the specific environment of the injected tumor cells. An active role of the environment on tumor progression was demonstrated e.g., for breast cancer (24)
.
On the basis of these observations we postulate: Colon carcinoma cells are still highly susceptible to exogenic regulation by the changing extracellular matrix, which may influence intracellular ß-catenin distribution and by cytokines like HGF, which also directly activate transcription factors. Different signals, depending on the changing tumor environment, converge at susceptible promoters and transiently activate relevant target genes. In dedifferentiated tumor cells at the invasive front, one of these genes transiently activated by nuclear ß-catenin and HGF is the laminin-5 2 chain, giving the tumor cells an ability to migrate and disseminate.
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ACKNOWLEDGMENTS |
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2 cDNA and promoter constructs. We also thank Ken Kinzler, Bert Vogelstein (Johns Hopkins University, Baltimore, MD), Hans Clevers (Dept. of Immunology, Univ. Medical Center, Utrecht, Netherlands), and Edgar Serfling (Dept. of Pathology, Univ. Würzburg, Würzburg, Germany) for various other DNA constructs and Friederike Pausch and Lydia Sorokin (Nikolaus Fiebiger Center, University of Erlangen, Erlangen, Germany) for help with in situ hybridization. For expert technical assistance we thank Ulrike Sudry and Claudia Knoll (Dept. of Pathology, Univ. of Erlangen, Erlangen, Germany). |
FOOTNOTES |
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1 Supported by Wilhelm-Sander-Stiftung Grant 99.065.1 (to T. B., A. J., and T. K.). 
2 These authors contributed equally to this publication.
3 To whom requests for reprints should addressed, at Department of Pathology, University of Erlangen-Nürnberg Krankenhausstr. 8-10, 91054 Erlangen, Germany. Phone: 49-9131-8522856; Fax: 49-9131-8524745; E-mail: thomas.brabletz{at}patho.imed.uni-erlangen.de
4 The abbreviations used are: BM, basal membrane; HGF, hepatocyte growth factor; APC, adenomatosis polyposis coli; TCF, T-cell factor; uPAR, urokinase-receptor; LAMC2, laminin 2 chain gene; AP, activator protein; dn, dominant negative.
Received 8/27/01. Accepted 10/ 3/01.
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REFERENCES |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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2 chain of kalinin/laminin 5 is preferentially expressed in invading malignant cells in human cancers. Am. J. Pathol., 145: 782-791, 1994.[Abstract]
2 chain gene (LAMC2) with activity in transgenic mice. Matrix Biol., 18: 197-210, 1999.[Medline]
2-chain gene promoter by hepatocyte growth factor (scatter factor). Biochem. J., 347: 407-417, 2000.[Medline]
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mark regions magnified in C and D. Magnifications are x40 (A and B), x100 (C and D), x400 (insets in C and D). In situ hybridization for laminin 
indicate wild-type promoter, 
, a promoter with both TCF sites mutated as indicated in Fig. 2A