Chaplet M, De Leval L, Waltregny D, Detry C, Fornaciari G, Bevilacqua G, Fisher L W, Castronovo V, Bellahcène A
Metastasis Research Laboratory, University of Liège, Liège, Belgium.
J Bone Miner Res. 2003 Aug;18(8):1506-12. doi: 10.1359/jbmr.2003.18.8.1506.
We have previously shown that breast and prostate cancers express bone matrix proteins. DMP1 expression was evaluated in 59 human lung cancer samples at the protein and mRNA levels. It was detectable in 80% of the cases, suggesting a potential role for DMP1 in tumor progression and bone metastasis.
Previously, we and others have shown that bone extracellular matrix proteins such as bone sialoprotein (BSP) and osteopontin (OPN) are expressed in various types of cancer that are characterized by a high affinity for bone including breast, prostate, and lung adenocarcinoma. Based on biochemical and genetic features, BSP, OPN, dentin matrix protein 1 (DMP1), and dentin sialophosphoprotein (DSPP) have been recently classified in a unique family named SIBLING (small integrin-binding ligand, N-linked glycoprotein). Therefore, we investigated whether DMP1 could also be detected in osteotropic cancers.
We first used a cancer array for evaluating the relative abundance of DMP1 transcript in a broad spectrum of human cancer tissues. This screening showed that DMP1 was strongly detectable in lung tumors compared with normal corresponding tissue. In a second step, we used an immunophosphatase technique and a specific polyclonal antibody directed against DMP1 to examine the expression of DMP1 in 59 human non-small cell lung cancer samples, including 29 squamous carcinoma, 20 adenocarcinoma, and 10 bronchioloalveolar carcinoma. Student's t-test was used to determine the statistical significance of immunostaining scores between the lung cancer histological groups studied and between cancer and normal lung tissues.
Our results show that DMP1 is detectable in 90% of the adenocarcinoma and squamous carcinoma analyzed while 8 of 10 bronchioloalveolar specimens were negative. DMP1 immunostaining intensity and extent scores were significantly higher in adenocarcinoma (p = 0.0004) and squamous carcinoma (p < 0.0001) samples compared with adjacent normal lung tissue. In situ hybridization experiments confirmed that DMP1 mRNA is localized in lung cancer cells.
In this study, we show that a third SIBLING protein is ectopically expressed in lung cancer. The role of DMP1 in lung cancer is largely unknown. Further studies are required to determine the implication of this protein, next to its sisters SIBLING proteins, in tumor progression and bone metastasis development.
我们之前已表明乳腺癌和前列腺癌会表达骨基质蛋白。在59例人类肺癌样本中对牙本质基质蛋白1（DMP1）的表达进行了蛋白质和mRNA水平的评估。在80%的病例中可检测到该蛋白，提示DMP1在肿瘤进展和骨转移中可能发挥作用。
此前，我们和其他人已表明，骨细胞外基质蛋白，如骨唾液蛋白（BSP）和骨桥蛋白（OPN），在各种对骨具有高亲和力的癌症中表达，包括乳腺癌、前列腺癌和肺腺癌。基于生化和遗传特征，BSP、OPN、牙本质基质蛋白1（DMP1）和牙本质涎磷蛋白（DSPP）最近被归为一个独特的家族，称为SIBLING（小整合素结合配体，N-连接糖蛋白）。因此，我们研究了在亲骨性癌症中是否也能检测到DMP1。
我们首先使用癌症芯片评估DMP1转录本在广泛的人类癌症组织中的相对丰度。该筛查显示，与相应正常组织相比，DMP1在肺肿瘤中可强烈检测到。第二步，我们使用免疫磷酸酶技术和针对DMP1的特异性多克隆抗体，检测59例人类非小细胞肺癌样本中DMP1的表达，其中包括29例鳞状细胞癌、20例腺癌和10例细支气管肺泡癌。采用学生t检验来确定所研究的肺癌组织学组之间以及癌组织与正常肺组织之间免疫染色评分的统计学意义。
我们的结果显示，在分析的腺癌和鳞状细胞癌中，90%可检测到DMP1，而10例细支气管肺泡样本中有8例为阴性。与相邻正常肺组织相比，腺癌（p = 0.0004）和鳞状细胞癌（p < 0.0001）样本中DMP1免疫染色强度和范围评分显著更高。原位杂交实验证实DMP1 mRNA定位于肺癌细胞中。
在本研究中，我们表明第三种SIBLING蛋白在肺癌中异位表达。DMP1在肺癌中的作用很大程度上未知。需要进一步研究来确定该蛋白及其SIBLING家族其他蛋白在肿瘤进展和骨转移发展中的意义。
