Uekita Takamasa, Tanaka Masamitsu, Takigahira Misato, Miyazawa Yuri, Nakanishi Yukihiro, Kanai Yae, Yanagihara Kazuyoshi, Sakai Ryuichi
National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Am J Pathol. 2008 Jun;172(6):1729-39. doi: 10.2353/ajpath.2008.070981. Epub 2008 May 8.
CUB-domain-containing protein 1 (CDCP1) is a type-I transmembrane protein that is highly expressed in colon, breast, and lung cancers. We recently revealed that CDCP1 is associated with and phosphorylated by Src family kinases and is involved in the regulation of anchorage independence of certain lung cancer cell lines. In this study, we examined whether CDCP1 is involved in the regulation of tumor progression of scirrhous gastric cancer, which is a diffusely infiltrative carcinoma with high invasion potential. Expression and phosphorylation levels of CDCP1 correlated with the invasive potential of scirrhous gastric cancers. Reduction of CDCP1 expression by siRNA suppressed migration, invasion, and anchorage independence without affecting the proliferation of highly invasive scirrhous gastric cancer cells. However, CDCP1 overexpression promoted gastric cancer cell migration with low potential of invasion. Loss of CDCP1 suppressed invasion and dissemination of cancer cells that were orthotopically implanted in the gastric wall of nude mice. Expression and phosphorylation of CDCP1 were also detected in cancer cells of surgically resected tissues of human scirrhous gastric cancer by immunohistochemical analysis. Our results suggest that CDCP1 promotes invasion and peritoneal dissemination of cancer cells through the regulation of cell migration and anchorage independence. Therefore, it is both a potential prognostic and therapeutic target in certain types of gastrointestinal cancers, and suppression of its phosphorylation might be a useful strategy for modulating cancer metastasis.
含CUB结构域蛋白1（CDCP1）是一种I型跨膜蛋白，在结肠癌、乳腺癌和肺癌中高表达。我们最近发现，CDCP1与Src家族激酶相关并被其磷酸化，且参与某些肺癌细胞系锚定非依赖性的调控。在本研究中，我们检测了CDCP1是否参与硬癌型胃癌的肿瘤进展调控，硬癌型胃癌是一种具有高侵袭潜能的弥漫浸润性癌。CDCP1的表达和磷酸化水平与硬癌型胃癌的侵袭潜能相关。通过小干扰RNA（siRNA）降低CDCP1表达可抑制高侵袭性硬癌型胃癌细胞的迁移、侵袭和锚定非依赖性，但不影响其增殖。然而，CDCP1过表达促进低侵袭潜能的胃癌细胞迁移。CDCP1缺失抑制原位植入裸鼠胃壁的癌细胞的侵袭和播散。通过免疫组织化学分析在人硬癌型胃癌手术切除组织的癌细胞中也检测到了CDCP1的表达和磷酸化。我们的结果表明，CDCP1通过调控细胞迁移和锚定非依赖性促进癌细胞的侵袭和腹膜播散。因此，它是某些类型胃肠道癌症潜在的预后和治疗靶点，抑制其磷酸化可能是调节癌症转移的一种有效策略。
