The cadherin-catenin adhesion system in signaling and cancer
The cadherin-catenin adhesion system in signaling and cancer
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DOI：
10.1172/jci200215429
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发表时间：
2002-04-01
影响因子：
15.9
通讯作者：
Ben-Ze'ev, A
中科院分区：
文献类型：
--
作者：
Conacci-Sorrell, M;Zhurinsky, J;Ben-Ze'ev, A
J. Clin. Invest. 109：987-991（2002）。DOI：10.1172/JCI 200215429。抑制其启动子。这些包括snail、E12/E47和SIP 1，它们与CDH 1启动子结合，抑制E-cad转录，并诱导上皮向间充质转化（EMT），导致获得侵袭性（9-12）。转录抑制子snail是一种锌指蛋白，最初被鉴定为发育中果蝇中中胚层形成的调节因子，最近被证明对小鼠发育中的EMT也至关重要。在人类癌和黑色素瘤中，snail的表达与E-cad表达的缺失相关。在培养的上皮细胞中snail的强制表达抑制CDH 1启动子并诱导侵袭性生长程序，其特征在于AJs的丧失和EMT和肿瘤发生的诱导（9，10）。有趣的是，小鼠皮肤肿瘤的侵袭性区域表达最高水平的snail，支持snail的激活赋予细胞侵袭性的观点（9）。E12/E47和SIP 1也抑制CDH 1启动子，同样可以诱导EMT，增加细胞运动性和侵袭性，并赋予致瘤性。此外，SIP 1表达在几种E-cad阴性人癌细胞中升高（11）。因此，癌细胞采用可逆或不可逆的机制来沉默E-cad的表达。这些机制可能有助于增强癌细胞的运动性和侵袭性。参与下调E-cad的转录机制类似于胚胎发育过程中典型阶段的特征，此时细胞粘附和运动发生变化。由于E-cad表达的丧失是许多类型的癌中的共同特征，并且由于E-cad重新引入癌细胞减少了侵袭和转移，因此靶向调节E-cad表达的癌症疗法可以提供控制癌症扩散的有力手段。最近的一项研究表明，维生素D3可诱导SW 480人结肠癌细胞中E-cad mRNA表达和细胞粘附（13）。这使得维生素D3成为通过抑制细胞生长来治疗结肠癌的潜在候选者，类似于其对黑色素瘤和软组织肉瘤的作用。
J. Clin. Invest. 109: 987–991 (2002). DOI: 10.1172/JCI200215429. repress its promoter. These include snail, E12/E47, and SIP1, which bind to the CDH1 promoter, inhibit E-cad transcription, and induce an epithelial-to-mesenchymal transition (EMT), leading to acquisition of invasiveness (9–12). The transcriptional repressor snail, a zinc finger protein originally identified as a regulator of mesoderm formation in developing Drosophila, was recently shown to be also critical for EMT in mouse development. In human carcinoma and melanoma, the expression of snail correlates with the absence of E-cad expression. Forced expression of snail in cultured epithelial cells represses the CDH1 promoter and induces a program of invasive growth characterized by the loss of AJs and the induction of EMT and tumorigenesis (9, 10). Interestingly, the invasive areas of mouse skin tumors express the highest levels of snail, supporting the view that activation of snail confers invasive properties on cells (9). E12/E47 and SIP1, which also repress the CDH1 promoter, can likewise induce EMT, increase cell motility and invasion, and confer tumorigenicity. Moreover, SIP1 expression is elevated in several E-cad–negative human carcinoma cells (11). Thus, cancer cells employ reversible or irreversible mechanisms to silence the expression of E-cad. These mechanisms may contribute to enhanced cancer cell motility and invasiveness. The transcriptional mechanisms involved in downregulation of E-cad are similar to those characteristic of typical stages during embryonic development, when changes in cell adhesion and motility take place. Since the loss of E-cad expression is a common feature in many types of carcinoma, and since E-cad reintroduction into cancer cells reduces invasion and metastasis, cancer therapies targeting the regulation of E-cad expression may offer powerful means to control the spread of cancer. A recent study demonstrated that E-cad mRNA expression and cellcell adhesion are induced in SW480 human colon cancer cells by vitamin D3 (13). This makes vitamin D3 a potential candidate for treating colon cancer by inhibiting cell growth, similar to its effect on melanoma and soft tissue sarcoma.