S100a2 As A Putative Tumour Suppressor

It is evident from the foregoing discussion that a majority of S100 family proteins appear to possess the ability to promote tumour progression by enhancing the proliferative and invasive potential of tumours. One member of the S100 protein family, namely S100A2, is believed to function as a tumour suppressor. S100A2 was isolated more than a decade ago by Glenney et al. (1989). It is found in certain cell types in the kidney, lung, and breast epithelium. It is moderately expressed in the liver, and cardiac and skeletal muscle, but not encountered in the adrenal gland, the intestine, or the brain. Lee et al. (1991) identified several cDNA clones that were highly expressed in normal tissues but suppressed in corresponding tumour-derived cells. Among these clones was a transcript of an S100 family gene. Subsequently, its expression was reported to be down-regulated in breast tumour cells. Exposure of these cells to 5-aza-2'-deoxycytidine produced a reexpression of this gene, which suggested that its expression was normally suppressed in the tumour cells by hyper-methylation (Lee et al. 1992). That hypermethylation of this gene is responsible for the loss of its expression in breast cancer cell lines has been confirmed recently (Wicki et al. 1997). A loss of S100A2 expression has been reported in several breast cancer cell lines (Pedrocchi et al. 1994). A marked loss of expression has been found in human sarcomas (E. Horvig, personal communication, 1998). S100A2 expression has been found in only 7% (of 107) of human sarcomas. In contrast, S100A4 and A6 expression was detected in 38 and 48%, respectively, of the specimens. This suggests a preponderant loss of S100A2 expression. However, there was no obvious correlation with clinical features or patient survival. In human astrocytomas also there is a conspicuous loss of S100A2 expression, whereas, in contrast, several other S100 proteins, notably S100A1, A4, and A6, are markedly expressed (Camby et al. 1999).

The suppressor function of S100A2, however, is not so clear-cut either in normal melanocytes or in melanomas. Thus, in normal melanocytes S100A2 is expressed at very low levels or is virtually undetectable. Neither is its expression up-regulated in malignant melanoma (L.B. Andersen et al. 1996). S100A2 staining has been reported in the basal layer of the epidermis and in hair follicles, but none has been found in naevi. Also, only a small proportion (4/39) of primary cutaneous melanomas and none of 14 metastatic lesions stained for S100A2 (Boni et al. 1997). A further report has appeared on S100A2 expression in epidermal cell types and epithelial tumours of the skin. Again the basal cells, epithelial cells of the sebaceous glands, and epithelial cells of hair follicles stained positive for S100A2. Also immunoreac-tive were basal cell as well as squamous cell carcinomas (Shrestha et al. 1998). Overall, the evidence available to date does not lend itself to a firm interpretation that S100A2 has a suppressor function or that its expression is associated with advanced stages of tumour progression. This view is also supported by the data published by Maelandsmo et al. (1997). The differences in the levels of S100A2 expression between naevi and cell lines derived from primary tumours seem to be more marked than those between the primary and metastatic lesions. This suggests that a down-regulation of the gene could occur in the early stages of development of these tumours. Xia et al. (1997) have cast further doubts about the suppressor function of S100A2. They found this gene to be highly expressed in basal and squamous cell carcinomas of the skin and oral cavity, although in situ hybridisation studies have indicated that the amounts of S100A2 occurring in the tumour cells themselves were limited. The majority of the protein was found in the hyperplastic epidermis around the tumour. Xia et al. (1997) found no differences in the expression of the protein in primary tumours and metastatic lesions.

Ilg et al. (1996) studied the binding of antibodies against several S100 proteins, including S100A2, and noticed a marked difference in their intracellular localisation. S100A2 was located predominantly in the nucleus, but S100A6 occurred mainly around the nucleus. They also found that the binding pattern of S100A2 antibodies differed from that of antibodies against S100A4, the expression of which has been widely reported to promote tumour-progression (see below). Although there is some evidence supporting the putative tumour suppressor function of S100A2, most of the research deals with its expression in tumour-derived cell lines, and there are no significant studies on the status of its expression in human tumours themselves.

The observation made by Xia et al. (1997) relating to the presence of S100A2 in hyperplastic epidermis incidentally serves to emphasise a putative relationship between the expression of this protein and the proliferative state of cells. This relationship now will seem more secure with the finding that EGF up-regulated S100A2 expression in organ cultures of human skin. EGF also markedly up-regulated the expression of S100A2 mRNA in immortalised human keratinocytes in culture. In both cases, the EGF effects could be blocked by using PD153035, which is a specific inhibitor of EGFr tyrosine kinase (Stoll et al. 1998). These experiments demonstrate the requirement of EGFr activation for the up-regulation of S100A2 expression, and therefore, suggest the presence of a direct relationship between S100A2 and mitogenic stimulation.

With this background of great ambiguity regarding the suppressor function of S100A2, one should look to some recent evidence that S100A2 function might be mediated by wild-type p53. Tan et al. (1999) have identified putative p53-binding sites in the promoter of S100A2. In vitro, wild-type p53 seems to transactivate S100A2. This transactivation is blocked by dominant negative p53 mutants. This can be deemed as evidence that S100A2 might influence cell proliferation with the mediation of p53. Thus p53 mediation may yet prove to be an underlying mechanism in the regulation of cell proliferation by S100 proteins.

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

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