Characterization of LMX-1A as a metastasis suppressor in cervical cancer.
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.
Liu
Chin-Yu
CY
Graduate Institute of Medical Sciences, National Defence Medical Center, Taipei, Taiwan, Republic of China.
Chao
Tai-Kuang
TK
Su
Po-Hsuan
PH
Lee
Hsin-Yi
HY
Shih
Yu-Lueng
YL
Su
Her-Young
HY
Chu
Tang-Yuan
TY
Yu
Mu-Hsien
MH
Lin
Ya-Wen
YW
Lai
Hung-Cheng
HC
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008648:Mesoderm / Q000503:physiopathology; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D010641:Phenotype; D011230:Precancerous Conditions / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D014183:Transplantation, Heterologous; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
C525809:BMP4 protein, human; C525816:BMP6 protein, human; D055415:Bone Morphogenetic Protein 4; D055418:Bone Morphogenetic Protein 6; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; C078021:LMX1A protein, human; D009363:Neoplasm Proteins; D014157:Transcription Factors