CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines.
CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines.
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DOI：
10.1186/bcr2215
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Chabannon C
中科院分区：
文献类型：
--
作者：
Zabouo G;Imbert AM;Jacquemier J;Finetti P;Moreau T;Esterni B;Birnbaum D;Bertucci F;Chabannon C
转移是一个复杂的过程，涉及癌细胞的黏附、迁移、侵袭和增殖。细胞黏附分子通过调节细胞-细胞和细胞-基质的相互作用在这一现象中起着关键作用。CD146(MCAM)与黑色素瘤、前列腺癌和卵巢癌的晚期肿瘤有关。关于CD146在乳腺癌中的表达和功能的研究仍然很少，除非有报道认为CD146在乳腺癌的发生中可能是一种肿瘤抑制因子。为了解决CD146在肿瘤细胞中作用的这些明显差异，我们使用DNA和组织微阵列研究了CD146在人类原发性乳腺癌中的表达与组织临床特征的关系。通过流式细胞仪检测CD146在不同乳腺癌细胞系中的表达。利用siRNA或shRNA技术，我们在迁移实验中研究了CD146下调MDA-MB-231细胞的功能后果。利用全基因组DNA芯片分析野生型、模拟转染组和下调转染组细胞的表达，以确定其表达受CD146下调的基因。微阵列研究揭示了较高水平的CD146与属于人类肿瘤基础簇的组织临床特征之间的关联。CD146蛋白在一小部分具有基底肿瘤组织临床特征的癌组织中表达。CD146+细胞系呈间充质表型。在MDA-MB-231细胞系中，CD146的表达下调导致波形蛋白的下调，以及一系列基因的下调，这些基因包括与各种癌症预后不良相关的基因和已知的促进细胞运动的基因。体外功能分析显示，CD146表达降低与细胞迁移能力降低有关。CD146除了在血管腔内表达外，在恶性乳腺上皮细胞亚群上也有表达。CD146可能通过促进恶性细胞的运动而直接或间接地促进肿瘤的侵袭性。CD146表达下调后分子特征的变化提示CD146下调与上皮向间充质转化相关的几个生物学特性的逆转以及与转移过程相关的现象有关。
Metastasis is a complex process involving loss of adhesion, migration, invasion and proliferation of cancer cells. Cell adhesion molecules play a pivotal role in this phenomenon by regulating cell–cell and cell–matrix interactions. CD146 (MCAM) is associated with an advanced tumor stage in melanoma, prostate cancer and ovarian cancer. Studies of CD146 expression and function in breast cancer remain scarce except for a report concluding that CD146 could act as a tumor suppressor in breast carcinogenesis. To resolve these apparent discrepancies in the role of CD146 in tumor cells, we looked at the association of CD146 expression with histoclinical features in human primary breast cancers using DNA and tissue microarrays. By flow cytometry, we characterized CD146 expression on different breast cancer cell lines. Using siRNA or shRNA technology, we studied functional consequences of CD146 downmodulation of MDA-MB-231 cells in migration assays. Wild-type, mock-transfected and downmodulated transfected cells were profiled using whole-genome DNA microarrays to identify genes whose expression was modified by CD146 downregulation. Microarray studies revealed the association of higher levels of CD146 with histoclinical features that belong to the basal cluster of human tumors. Expression of CD146 protein on epithelial cells was detected in a small subset of cancers with histoclinical features of basal tumors. CD146+ cell lines displayed a mesenchymal phenotype. Downmodulation of CD146 expression in the MDA-MB-231 cell line resulted in downmodulation of vimentin, as well as of a set of genes that include both genes associated with a poor prognosis in a variety of cancers and genes known to promote cell motility. In vitro functional assays revealed decreased migration abilities associated with decreased CD146 expression. In addition to its expression in the vascular compartment, CD146 is expressed on a subset of epithelial cells in malignant breast. CD146 may directly or indirectly contribute to tumor aggressiveness by promoting malignant cell motility. Changes in molecular signatures following downmodulation of CD146 expression suggest that CD146 downmodulation is associated with the reversal of several biological characteristics associated with epithelial to mesenchymal transition, and the phenomenon associated with the metastatic process.
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