Rohde Franziska, Rimkus Caroline, Friederichs Jan, Rosenberg Robert, Marthen Carmen, Doll Dietrich, Holzmann Bernhard, Siewert Jörg-Rüdiger, Janssen Klaus-Peter
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Int J Cancer. 2007 Oct 15;121(8):1717-23. doi: 10.1002/ijc.22868.
Osteopontin (OPN) is a secreted phosphoprotein, which has been reported to be associated with tumor progression in numerous solid tumors. In a previous transcriptome study on colorectal cancer, we identified the gene OPN among the most strongly up-regulated transcripts. OPN has been suggested as a putative target of Wnt signaling, but the molecular mechanism responsible for its aberrant transcription is not fully understood. We analyzed 13 normal colon tissues, 9 adenomas, 120 primary colon tumors, and 10 liver metastases by quantitative reverse-transcription PCR. OPN expression was strongly elevated in primary colon cancer and liver metastasis, but not in pre-cancerous lesions and UICC stage I tumors. Multivariate analysis established OPN expression as an independent prognostic parameter for overall survival. Moreover, high OPN expression identified a subgroup of patients with bad prognosis. Next, we determined immunohistochemically a correlation of OPN expression with aberrant beta-catenin staining, which is indicative of Wnt activation. Elevated expression of OPN was significantly correlated with increased cytoplasmic and nuclear beta-catenin staining. The in vivo role of Wnt signaling for the expression of OPN was tested in genetically defined mouse models with (Apc(1638N)) or without (pvillin-KRAS(V12G)) Wnt activating mutations. Mutation of the tumor suppressor APC was necessary for upregulation of OPN expression in the murine tumors on transcript and on protein levels. Thus, OPN is a transcriptional target of aberrant Wnt signaling, and OPN expression alone predicts survival in human colon cancer.
骨桥蛋白（OPN）是一种分泌型磷蛋白，据报道在多种实体瘤中与肿瘤进展相关。在先前一项关于结直肠癌的转录组研究中，我们在上调最为强烈的转录本中鉴定出了OPN基因。OPN被认为是Wnt信号通路的一个假定靶点，但其异常转录的分子机制尚未完全明确。我们通过定量逆转录PCR分析了13个正常结肠组织、9个腺瘤、120个原发性结肠肿瘤和10个肝转移灶。OPN表达在原发性结肠癌和肝转移灶中显著升高，但在癌前病变和国际抗癌联盟（UICC）I期肿瘤中未升高。多变量分析将OPN表达确立为总生存期的一个独立预后参数。此外，高OPN表达确定了一组预后不良的患者亚群。接下来，我们通过免疫组织化学确定了OPN表达与异常β-连环蛋白染色之间的相关性，后者表明Wnt激活。OPN表达升高与细胞质和细胞核β-连环蛋白染色增加显著相关。在具有（Apc(1638N)）或不具有（pvillin-KRAS(V12G)）Wnt激活突变的基因定义小鼠模型中测试了Wnt信号通路对OPN表达的体内作用。肿瘤抑制因子APC的突变对于小鼠肿瘤中OPN表达在转录水平和蛋白水平的上调是必需的。因此，OPN是异常Wnt信号通路的一个转录靶点，仅OPN表达就能预测人类结肠癌的生存期。
