Santin Alessandro D, Cane' Stefania, Bellone Stefania, Bignotti Eliana, Palmieri Michela, De Las Casas Luis E, Anfossi Simone, Roman Juan J, O'Brien Timothy, Pecorelli Sergio
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Cancer. 2003 Nov 1;98(9):1898-904. doi: 10.1002/cncr.11753.
Tumor-associated differentially expressed gene-15 (TADG-15/matriptase/MT-SP1) is a novel transmembrane serine protease involved in numerous biologic processes, including activation of growth and angiogenic factors and degradation of extracellular matrix components. To assess the value of TADG-15 as a possible marker for tumor detection and/or as a target for therapeutic intervention, the authors investigated the frequency of expression of TADG-15 in human cervical tumors.
TADG-15 expression was evaluated in 19 cervical carcinoma cell lines (i.e., 11 primary tumor cell lines and 8 established cell lines) and in 8 normal cervical keratinocyte control cultures using reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, to validate gene expression data at the protein level, TADG-15 expression was evaluated by immunohistochemistry on paraffin embedded tissue from which all 11 primary tumor cell lines were established.
TADG-15 was expressed at high levels in 8 of 11 (73%) primary cervical carcinoma cell lines and in 6 of 8 (75%) established cervical carcinoma cell lines by RT-PCR. Expression of TADG-15 was found in 6 of 6 (100%) primary squamous cell cervical carcinomas, whereas 2 of 5 (40%) primary adenocarcinomas expressed TADG-15. In contrast, none of the normal cervical keratinocyte control cultures (n = 4) or flash-frozen normal cervical biopsy specimens (n = 4) expressed TADG-15. Immunohistochemistry staining of paraffin embedded cervical carcinoma specimens confirmed TADG-15 expression in tumor cells and its absence on normal cervical epithelial cells.
Cervical carcinoma cells expressed high levels of TADG-15, suggesting that this protease may play an important role in invasion and metastasis. Because TADG-15 appears only in abundance in squamous tumor tissue and contains a proteolytic cleavage site, suggesting that the TADG-15 protease domain is released, it may prove to be a useful diagnostic tool for the early detection of recurrent/persistent cervical carcinoma after standard treatment or as a novel molecular target for therapy in patients with cervical carcinoma.
肿瘤相关差异表达基因-15（TADG-15/胃蛋白酶/MT-SP1）是一种新型跨膜丝氨酸蛋白酶，参与众多生物学过程，包括生长因子和血管生成因子的激活以及细胞外基质成分的降解。为了评估TADG-15作为肿瘤检测的可能标志物和/或治疗干预靶点的价值，作者研究了TADG-15在人宫颈肿瘤中的表达频率。
使用逆转录聚合酶链反应（RT-PCR）在19种宫颈癌细胞系（即11种原发性肿瘤细胞系和8种已建立的细胞系）以及8种正常宫颈角质形成细胞对照培养物中评估TADG-15的表达。此外，为了在蛋白质水平验证基因表达数据，通过免疫组织化学对建立所有11种原发性肿瘤细胞系的石蜡包埋组织进行TADG-15表达评估。
通过RT-PCR，11种原发性宫颈癌细胞系中的8种（73%）和8种已建立的宫颈癌细胞系中的6种（75%）高水平表达TADG-15。在6种（100%）原发性宫颈鳞状细胞癌中发现TADG-15表达，而5种原发性腺癌中有2种（40%）表达TADG-15。相比之下，正常宫颈角质形成细胞对照培养物（n = 4）或快速冷冻的正常宫颈活检标本（n = 4）均未表达TADG-15。石蜡包埋的宫颈癌标本的免疫组织化学染色证实肿瘤细胞中TADG-15表达，而正常宫颈上皮细胞中无表达。
宫颈癌细胞高水平表达TADG-15，提示该蛋白酶可能在侵袭和转移中起重要作用。由于TADG-15仅在鳞状肿瘤组织中大量出现且含有蛋白水解切割位点，提示TADG-15蛋白酶结构域被释放，它可能被证明是标准治疗后早期检测复发性/持续性宫颈癌的有用诊断工具，或作为宫颈癌患者治疗的新型分子靶点。
