Reichrath Jörg, Welter Cornelius, Mitschele Tanja, Classen Ulf, Meineke Viktor, Tilgen Wolfgang, Seifert Markus
Department of Dermatology, University of Saarland, Homburg, Germany.
J Pathol. 2003 Apr;199(4):509-16. doi: 10.1002/path.1308.
Calpain, also named CAPN (for calcium-activated neutral protease), is a ubiquitous intracellular cytoplasmic non-lysosomal cysteine endopeptidase that requires calcium ions to exert its activity. Two major isoenzymes are known- micro -calpain (CAPN1) and m-calpain (CAPN2)-requiring micromolar and millimolar calcium concentrations for activation, respectively. Many known substrates of the different calpain isoenzymes, such as the transcription factors c-Fos and c-Jun, the tumour suppressor protein p53, protein kinase C, pp60src, or the adhesion molecule integrin, have been implicated in the pathogenesis of various malignancies including squamous (SCC) and basal (BCC) cell carcinomas of human skin, suggesting an important role of the calpain isoenzymes in malignant diseases. We have analysed the expression of CAP1 and CAPN2 protein and mRNA expression in BCCs and SCCs of human skin. Interestingly, CAPN1 immunoreactivity (streptavidin-peroxidase technique) was markedly reduced in BCCs compared to normal human skin or SCCs, while in contrast CAPN1 mRNA levels (determined by real-time PCR) were markedly elevated in BCCs and SCCs compared to normal human skin. No differences were found analysing CAPN2 protein and mRNA expression in normal human skin, BCCs and SCCs. In conclusion, we have demonstrated for the first time alterations in calpain mRNA expression and protein content in malignant skin tumours that may be of importance for the tumorigenesis and growth characteristics of BCCs and SCCs. However, our results do not allow conclusions on the function of CAPN1 and CAPN2 in BCCs and SCCs. It is not known if the CAPN genes in BCCs or SCCs exhibit functionally inactivating mutations or whether decreased CAPN1 protein expression in BCCs and elevated CAPN1 mRNA in BCCs and SCCs reflect a feedback loop coupled with increased degradation or proteolysis of CAPN1 protein.
钙蛋白酶，也称为CAPN（钙激活中性蛋白酶），是一种普遍存在于细胞内细胞质中的非溶酶体半胱氨酸内肽酶，其发挥活性需要钙离子。已知有两种主要的同工酶——微钙蛋白酶（CAPN1）和m-钙蛋白酶（CAPN2），分别需要微摩尔和毫摩尔浓度的钙离子来激活。不同钙蛋白酶同工酶的许多已知底物，如转录因子c-Fos和c-Jun、肿瘤抑制蛋白p53、蛋白激酶C、pp60src或黏附分子整合素，都与包括人类皮肤鳞状细胞癌（SCC）和基底细胞癌（BCC）在内的各种恶性肿瘤的发病机制有关，这表明钙蛋白酶同工酶在恶性疾病中起重要作用。我们分析了CAP1和CAPN2蛋白在人类皮肤BCC和SCC中的表达以及mRNA表达。有趣的是，与正常人类皮肤或SCC相比，BCC中CAPN1免疫反应性（链霉亲和素-过氧化物酶技术）明显降低，而相比之下，与正常人类皮肤相比，BCC和SCC中CAPN1 mRNA水平（通过实时PCR测定）明显升高。在分析正常人类皮肤、BCC和SCC中CAPN2蛋白和mRNA表达时未发现差异。总之，我们首次证明了恶性皮肤肿瘤中钙蛋白酶mRNA表达和蛋白含量的改变，这可能对BCC和SCC的肿瘤发生和生长特征具有重要意义。然而，我们的结果无法得出关于CAPN1和CAPN2在BCC和SCC中的功能的结论。目前尚不清楚BCC或SCC中的CAPN基因是否表现出功能失活突变，或者BCC中CAPN1蛋白表达降低以及BCC和SCC中CAPN1 mRNA升高是否反映了与CAPN1蛋白降解或蛋白水解增加相关的反馈回路。
