Characterization of LMX‐1A as a metastasis suppressor in cervical cancer

• DOI: 10.1002/path.2589
• Publication Date: 2009-06-16T08:57:17Z
• Authors: Chin‐Yu Liu; Tai‐Kuang Chao; Po‐Hsuan Su; Hsin‐Yi Lee; Yu‐Lueng Shih; Her‐Young Su; Tang‐Yuan Chu; Mu‐Hsien Yu; Ya‐Wen Lin; Hung‐Cheng Lai
• Keywords: Homeodomain Proteins; 0301 basic medicine; Bone Morphogenetic Protein 6; LIM-Homeodomain Proteins; Epithelial Cells; Bone Morphogenetic Protein 4; Mice, SCID; Neoplasm Proteins; 3. Good health; Gene Expression Regulation, Neoplastic; Mesoderm; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Cell Line, Tumor; Disease Progression; Animals; Humans; Female; Genes, Tumor Suppressor; Neoplasm Invasiveness; Gene Silencing; Neoplasm Metastasis

AbstractDNA 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 TGFβ–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 © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.