He B, Mirza M, Weber G F
Molecular Oncology Research Institute, New England Medical Center, Boston, MA, USA.
Oncogene. 2006 Apr 6;25(15):2192-202. doi: 10.1038/sj.onc.1209248.
In malignant tumors, metastasis genes are typically deregulated by aberrant expression or splicing. Osteopontin is expressed at high levels by various cancers and contributes importantly to their invasive potential. In contrast, osteopontin derived from host cells induces cellular immunity and could bolster antitumor protection by cytotoxic T lymphocytes. Here we show that breast cancer cells express multiple splice variants of osteopontin. According to RT-PCR analysis of human breast tissue specimens, the splice variant osteopontin-c is a highly specific marker for transformed cells, which is not expressed in their surrounding normal tissue. The full-length form of osteopontin aggregates in the presence of physiologic amounts of calcium and, in this state, leads to enhanced cell adhesion. Ostensibly, this effect is inhibitory for tumor cell dissemination. The shortest splice variant, osteopontin-c, does not aggregate in the presence of calcium and enhances clone formation in soft agar. According to microarray analysis, osteopontin-c induces the expression of oxidoreductases, consistent with protection from anoikis during anchorage-independent growth. These studies define a third functional domain of osteopontin, beside the C-terminal CD44-binding site and the central integrin-binding site. They also provide evidence for a bifunctional character of osteopontin, with the soluble form supporting invasiveness and the aggregated form promoting adhesion.
在恶性肿瘤中，转移基因通常因异常表达或剪接而失调。骨桥蛋白在多种癌症中高表达，并对其侵袭潜能有重要贡献。相比之下，宿主细胞来源的骨桥蛋白可诱导细胞免疫，并可增强细胞毒性T淋巴细胞的抗肿瘤保护作用。在此我们表明，乳腺癌细胞表达多种骨桥蛋白剪接变体。根据对人乳腺组织标本的逆转录聚合酶链反应（RT-PCR）分析，剪接变体骨桥蛋白-c是转化细胞的高度特异性标志物，在其周围正常组织中不表达。骨桥蛋白的全长形式在生理量钙存在的情况下会聚集，在此状态下会导致细胞黏附增强。显然，这种作用对肿瘤细胞的扩散具有抑制作用。最短的剪接变体骨桥蛋白-c在钙存在的情况下不会聚集，并且会增强软琼脂中的克隆形成。根据微阵列分析，骨桥蛋白-c可诱导氧化还原酶的表达，这与在非锚定依赖性生长过程中免受失巢凋亡的保护作用一致。这些研究确定了骨桥蛋白的第三个功能域，位于C末端CD44结合位点和中央整合素结合位点之外。它们还为骨桥蛋白的双功能特性提供了证据，即可溶性形式支持侵袭性，而聚集形式促进黏附。
