Department of Molecular Cytogenetics, Tokyo Medical and Dental University, Tokyo, Japan.
Oncogene. 2012 Nov 22;31(47):4923-34. doi: 10.1038/onc.2011.646. Epub 2012 Jan 30.
Epithelial-mesenchymal transition (EMT) has a major role in cancer progression, as well as normal organ development and human pathology such as organ fibrosis and wound healing. Here, we performed a gene expression array specialized in EMT of colorectal cancer (CRC). From a comprehensive gene expression analysis using epithelial- and mesenchymal-like CRC cell lines, and following the ontology (GO) analysis, SIX1 gene was identified to be an EMT-related gene in CRC. Using SW480 cells stably transfected with a SIX1 expression construct and their control counterparts, we demonstrated that SIX1 overexpression represses CDH1 expression and promotes EMT in CRC. SIX1-induced CDH1 repression and EMT in CRC cells were correlated at least in part with posttranscriptional ZEB1 activation and miR-200-family transcriptional repression. In primary tumors of CRC, in accord with the functional findings, aberrant expression of SIX1 in cancer cells was observed at the disruption of the basement membrane and at the tumor invasive front, where tumor cells underwent EMT in vivo. Taken together, SIX1 overexpression is suggested to occur in carcinogenesis, and contribute to repression of CDH1 expression and promotion of EMT partly through repression of miR-200-family expression and activation of ZEB1 in CRC.
上皮-间充质转化（EMT）在癌症进展中起着重要作用，也在正常器官发育和人类病理学中发挥作用，如器官纤维化和伤口愈合。在这里，我们进行了一项专门针对结直肠癌（CRC）EMT 的基因表达谱分析。通过对上皮样和间充质样 CRC 细胞系进行全面的基因表达分析，并进行本体论（GO）分析，我们确定 SIX1 基因是 CRC 中的 EMT 相关基因。使用稳定转染 SIX1 表达构建体的 SW480 细胞及其对照物，我们证明 SIX1 过表达抑制 CDH1 表达并促进 CRC 中的 EMT。SIX1 诱导的 CRC 细胞中 CDH1 抑制和 EMT 至少部分与转录后 ZEB1 激活和 miR-200 家族转录抑制相关。在 CRC 的原发性肿瘤中，与功能发现一致，在基底膜的破坏和肿瘤侵袭前沿观察到癌细胞中 SIX1 的异常表达，在体内肿瘤细胞经历 EMT。总之，SIX1 的过表达似乎发生在癌变过程中，并通过抑制 miR-200 家族的表达和激活 ZEB1 来部分抑制 CDH1 表达和促进 EMT，从而促进 CRC 的发生。
