State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Am J Pathol. 2011 Jul;179(1):380-90. doi: 10.1016/j.ajpath.2011.03.046. Epub 2011 May 23.
P-cadherin belongs to the family of classic cadherins, which is important for maintaining cellular localization and tissue integrity. Recently, it has become evident that P-cadherin contributes to the oncogenesis of many tumor types, including melanoma, prostate, breast, and colon carcinomas. Although cadherin switching is a crucial step in metastasis, the role of P-cadherin in colon cancer metastasis to the liver is unknown. In this study, we performed gene expression analysis and found that the level of P-cadherin was higher in tissue from liver metastases of colon cancer than in the corresponding primary colon cancer tissues. IHC analysis also showed that P-cadherin expression was significantly higher in liver metastases than in paired primary colorectal cancer tumors. Knockdown of P-cadherin in colon cancer cells inhibited wound healing, proliferation, and colony formation and resulted in developing fewer liver metastatic foci and reducing the tumor burden in vivo. Inhibition of P-cadherin expression also induced the up-regulation of E-cadherin and the down-regulation of β-catenin and its downstream target molecules, including survivin and c-Myc. In summary, these results uncover a novel function of P-cadherin in the regulation of colon cancer metastasis to the liver, suggesting that blocking the activity of P-cadherin or its associated signaling may be a valuable target for the treatment of hepatic metastases of colon carcinomas.
P-钙黏蛋白属于经典钙黏蛋白家族，对于维持细胞定位和组织完整性非常重要。最近，人们已经意识到 P-钙黏蛋白参与了许多肿瘤类型的发生，包括黑色素瘤、前列腺癌、乳腺癌和结肠癌。尽管钙黏蛋白转换是转移的关键步骤，但 P-钙黏蛋白在结肠癌转移到肝脏中的作用尚不清楚。在这项研究中，我们进行了基因表达分析，发现结肠癌肝转移组织中 P-钙黏蛋白的水平高于相应的原发性结肠癌组织。免疫组化分析还表明，P-钙黏蛋白在肝转移中表达明显高于配对的原发性结直肠癌肿瘤。在结肠癌细胞中敲低 P-钙黏蛋白抑制了伤口愈合、增殖和集落形成，导致形成的肝转移灶更少，并减少了体内的肿瘤负担。抑制 P-钙黏蛋白的表达还诱导了 E-钙黏蛋白的上调和β-连环蛋白及其下游靶分子，包括存活素和 c-Myc 的下调。总之，这些结果揭示了 P-钙黏蛋白在调节结肠癌转移到肝脏中的新功能，表明阻断 P-钙黏蛋白或其相关信号通路的活性可能是治疗结肠癌肝转移的有价值的靶点。
