DNA甲基化在肿瘤发生中非常重要,并有望成为肿瘤检测的生物标记.我们先前的研究表明LMX-1A在宫颈瘤中为甲基化-沉默.LMX-1A为LIM同源异型基因,他主要参与发育事件,但是到目前为止并没有该基因与肿瘤相关的数据.在本研究中,我们在细胞系、动物模型和人宫颈瘤组织中鉴定了该转录因子的功能,研究表明：过表达LMX-1A对人宫颈瘤细胞的增殖和细胞周期没有影响,但是它能在体外显著抑制人宫颈瘤细胞群的形成和入侵作用.通过分析上皮细胞-间叶细胞迁移（EMT）标记物（如：CDH1、CDH2、WIMENTIN、SNAIL、SLUG和TWIST）的改变发现EMT与LMX-1A调节的癌细胞迁移有关,这个结果在LMX-1A过表达稳定系中进行RNAi得到了证实.移植人宫颈瘤细胞到免疫低下小鼠同样发现LMX-1A对肿瘤形成和远端转移有抑制作用.组织芯片免疫组化分析LMX-1A表达发现LMX-1A在宫颈瘤细胞入侵和转移中起关键作用,该芯片包含有正常的子宫颈、低度子宫颈上皮瘤,、高度子宫颈上皮瘤,局部侵入的子宫颈上皮瘤以及远端转移癌.这些结果表明：在宫颈癌中LMX-1A通过不完全的EMT抑制肿瘤细胞的入侵和转移.

  Characterization of LMX-1A as a metastasis suppressor in cervical cancer.
  Liu CY, Chao TK, Su PH, Lee HY, Shih YL, Su HY, Chu TY, Yu MH, Lin YW, Lai HC.
  Graduate Institute of Medical Sciences, National Defence Medical Center, Taipei, Taiwan, Republic of China.
  DNA methylation is important in cancer development and is a promising biomarker for cancer detection. An epigenomic approach used in our previous work showed that LMX-1A is methylation-silenced in cervical cancer. LMX-1A, a LIM-homeobox gene, is known to participate in developmental events; however, there are at present no data on the role of LMX-1A in cancers. In this study, we characterized the function of this transcription factor by examining cell lines, animal models and human cervical neoplastic tissues, and found that over-expression of LMX-1A does not affect cell proliferation or the cell cycle of cervical cancer cell lines but significantly inhibits colony formation and invasion in vitro. Analysis of changes in epithelial-mesenchymal transition (EMT) markers, such as CDH1, CDH2, VIMENTIN, SNAIL, SLUG and TWIST, revealed involvement of the EMT in LMX-1A-mediated cancer invasion; this result was validated in a stable transfectant over-expressing LMX-1A with RNA interference. Xenograft studies using immunocompromised mice confirmed the suppressor effects of LMX-1A on tumour formation and distant metastasis in cervical cancer cell lines. LMX-1A immunohistochemical staining of tissue arrays containing the full spectrum of cervical neoplasms, including normal cervix, low-grade cervical intra-epithelial neoplasia (CIN), high-grade CIN, locally invasive and distant metastatic cancers, demonstrated the critical role of LMX-1A in invasion and metastasis. Furthermore, we found by analysing TGFbeta-BMP signalling that BMP4 and BMP6 are down-regulated by LMX-1A. The results of this study suggest that LMX-1A suppresses cancer invasion and metastasis in cervical cancer through an incomplete EMT. Copyright (c) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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