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S100A2, a Putative Tumor Suppressor Gene, Regulates in Vitro

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S100A2, a Putative Tumor Suppressor Gene, Regulates in Vitro 0023-6837/01/8104-599$03.00/0 LABORATORY INVESTIGATION Vol. 81, No. 4, p. 599, 2001 Copyright © 2001 by The United States and Canadian Academy of Pathology, Inc. Printed in U.S.A. S100A2, a Putative Tumor Suppressor Gene, Regulates In Vitro Squamous Cell Carcinoma Migration Nathalie Nagy, Carmen Brenner, Nicolas Markadieu, Carole Chaboteaux, Isabelle Camby, Beat W. Schäfer, Roland Pochet, Claus W. Heizmann, Isabelle Salmon, Robert Kiss, and Christine Decaestecker Department of Pathology (NN, IS), Erasmus University Hospital, and Laboratories of Molecular Virology (CB) and Histopathology (NM, CC, IC, RP, RK, CD), Faculty of Medicine; Université Libre de Bruxelles, Brussels, Belgium; Division of Clinical Chemistry and Biochemistry (BWS, CWH), Department of Pediatrics, University of Zürich, Zürich, Switzerland; and Fonds National de la Recherche Scientifique (RK, CD), Brussels, Belgium SUMMARY: It has been previously shown that S100A2 is down-regulated in tumor cells and can be considered a tumor suppressor. We have recently shown that this down-regulation can be observed particularly in epithelial tissue, where S100A2 expression decreases remarkably in tumors as compared with normal specimens. In the present paper we investigate whether S100A2 could play a tumor-suppressor role in certain epithelial tissues by acting at the cell migration level. To this end, we made use of five in vitro human head and neck squamous cell carcinoma lines in which we characterized S100A2 expression at both RNA and protein level. To characterize the influence of S100A2 on cell kinetic and cell motility features, we used two complementary approaches involving specific antisense oligonucleotides and the addition of S100A2 to the culture media. The different expression analyses gave a coherent demonstration of the fact that the FADU and the RPMI-2650 cell lines exhibit high and low levels of S100A2 expression, respectively. Antisense oligonucleotides (in FADU) and extracellular treatments (in RPMI) showed that, for these two models, S100A2 had a clear inhibitory influence on cell motility while modifying the cell kinetic parameters only slightly. These effects seem to be related, at least in part, to a modification in the polymerization/ depolymerization dynamics of the actin microfilamentary cytoskeleton. Furthermore, we found evidence of the presence of the receptor for advanced glycation end-products (RAGE) in RPMI cells, which may act as a receptor for extracellular S100A2. The present study therefore presents experimentally based evidence showing that S100A2 could play a tumor-suppressor role in certain epithelial tissues by restraining cell migration features, at least in the case of head and neck squamous cell carcinomas. (Lab Invest 2001, 81:599–612). alcium regulates a variety of biological pro- Heizmann and Cox, 1998; Schäfer and Heizmann, C cesses as a second messenger, and Ca2ϩ sig- 1996). To date, some 19 different proteins have been nals are transduced into intracellular responses via an assigned to the S100 protein family, and the genes interaction with numerous Ca2ϩ-binding proteins encoding more than ten S100 proteins are located in a characterized by the EF-hand motif (Donato, 1999; cluster on human chromosome 1q21 (Schäfer and Schäfer and Heizmann, 1996). The biological pro- Heizmann, 1996). cesses upon which calcium exerts a significant influ- S100A2 is of particular interest because its cDNA ence include cell proliferation, cell migration, and coding was identified in a search for novel tumor- muscle contraction (Donato 1999; Gimona et al, 1997; suppressor genes as the result of subtractive hybrid- Schäfer and Heizmann, 1996). The family of S100 ization between normal and tumor-derived human proteins has grown to be one of the largest superfami- mammary epithelial cells (Lee et al, 1991). Extending lies of EF-hand proteins since the first S100 protein this observation to breast tumors, Lee et al (1992) was identified from brain tissue more than 30 years showed a marked down-regulation of S100A2 in 2ϩ ago as an acidic, low-molecular-mass, Ca -binding breast tumor biopsies. In the same way, we have protein (Moore, 1965). The physiological and struc- shown that, whereas no expression of the S100A2 tural properties of S100 proteins suggest that they are gene could be detected on 11 tumorigenic human 2ϩ trigger or activator proteins, whereas other Ca - breast epithelial cell lines, a normal breast epithelial binding proteins act mainly as buffers (Donato, 1999; cell line and biopsy specimens did express S100A2 (Pedrocchi et al, 1994). The down-regulation of Received January 22, 2001. S100A2 is not restricted to breast cancer but is also Address reprint requests to: Dr. Christine Decaestecker, Laboratory of found in melanomas (Maelandsmo et al, 1997) and Histopathology, Faculty of Medicine, Université Libre de Bruxelles, 808 other tumor types (Ilg et al, 1996). All these data have route de Lennik, 1070 Brussels, Belgium. E-mail: [email protected] thus led to the designation of the S100A2 gene as a Laboratory Investigation • April 2001 • Volume 81 • Number 4 599 Nagy et al Figure 1. 600 Laboratory Investigation • April 2001 • Volume 81 • Number 4 S100A2 Influence on Cell Carcinoma Migration tumor suppressor, and S100A2 might therefore be literature (Komada et al, 1996). We also investigated generally down-regulated when cells acquire a tumor- the presence of the receptor for advanced glycation igenic phenotype, a factor which implies that the end products (RAGE), a candidate receptor for S100/ protein may play a role in inhibiting tumor progression calgranulin polypeptides (Hofmann et al, 1999), which or suppressing tumor cell growth (Wicki et al, 1997). In we found evidence of particularly in the RPMI model. addition, the expression of S100A2 can be induced by growth factors (Lee et al, 1992; Stoll et al, 1998). For Results example, epidermal growth factor (EGF) receptor ac- tivation selectively stimulates S100A2 gene expres- S100A2 Expression in Five In Vitro Models of Human Squamous Cell Carcinomas sion at the transcriptional level in human keratinocytes (Stoll et al, 1998). Taking the five HNSCC cell lines analyzed, Figure 2, A In a recent study (N Nagy, D Hoyaux, I Gielen, BW and B, illustrates the results obtained by RT-PCR (A) to Schafer, R Pochet, CW Heizmann, R Kiss, I Salmon, reveal the presence of S100A2 mRNAs and by Western and C Decaestecker, unpublished data), we charac- blotting (B) to show S100A2 expression at the protein terized the level of immunohistochemical S100A2 ex- level. To confirm and refine these first results, quantita- pression in a large set of normal and tumoral (benign tive analyses of S100A2 expression were undertaken by and malignant) tissues of various histological origins, means of computer-assisted microscopy applied to but epithelial in the great majority of cases (with either conventional immunohistochemistry. In Figure 2C, the glandular, squamous, respiratory, or urothelial differ- labeling index (LI) reports the percentage of immunopo- entiation). The data show that S100A2 is expressed sitive cells, and in Figure 2D, the mean optical density only marginally, if at all, in nonepithelial tissue. In (MOD) denotes staining intensity computed on the im- epithelial tissue its level of expression decreases dra- munopositive cells only. Because of standardization (see matically in tumors compared with normal specimens “Materials and Methods”), these two variables enable a (Fig. 1, A and B). We also showed that S100A2 is precise quantitative evaluation and comparison of colocated with cytokeratin K14, an intermediate fila- S100A2 expression to be established in the five cell lines ment protein characteristic of epithelial cells, which is analyzed. All of these data give a consistent representa- expressed in basal proliferative keratinocytes. tion of the different levels of S100A2 expression encoun- The present study aims to investigate whether tered in the five cell lines analyzed. Of these, the FADU S100A2 could play its tumor-suppressor role in epi- and RPMI models exhibited particularly high and low thelium tissue by acting at the cell-migration level. To levels of S100A2 expression, respectively. This is why this end, we first characterized the S100A2 expression we chose these two models to investigate the influence levels in five in vitro human head and neck squamous of S100A2 on HNSCC cell kinetic and migration proper- cell carcinoma (HNSCC) lines (the FADU, Det-562, ties, as reported below. RPMI, SCC-9, and SCC-25 models). This was done at the RNA level by means of reverse transcription- S100A2 Inhibition in FADU Cells by Means of Specific polymerase chain reaction (RT-PCR) and at the pro- Antisense Oligonucleotides tein level by means of Western blotting and immuno- histochemistry. Two models (FADU and RPMI) We chose the FADU and the RPMI cell lines as biological expressing S100A2 at a high and a low level, respec- models. As reported above, while the RPMI model tively, were selected on the basis of the results ob- shows a relatively low level of expression, the FADU tained. The influence of S100A2 on these two models model shows a high one. We accordingly analyzed the was then analyzed at the cell kinetic and cell motility effects of S100A2 inhibition in the FADU cells by means levels. This was carried out in two complementary of antisense oligonucleotides and S100A2 added exter- ways: S100A2 expression was inhibited in the FADU nally to the RPMI cells (see below). model (high natural expression)
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