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

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

Research output: Contribution to journalArticle

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Abstract

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 overexpressing 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.

Original languageEnglish
Pages (from-to)222-231
Number of pages10
JournalJournal of Pathology
Volume219
Issue number2
DOIs
Publication statusPublished - Oct 2009
Externally publishedYes

Fingerprint

Uterine Cervical Neoplasms
Neoplasm Metastasis
Epithelial-Mesenchymal Transition
Neoplasms
Cell Line
Gastropoda
Homeobox Genes
Snails
Vimentin
DNA Methylation
Tumor Biomarkers
RNA Interference
Heterografts
Epigenomics
Cervix Uteri
Methylation
Cell Cycle
Transcription Factors
Animal Models
Cell Proliferation

Keywords

  • Cancer
  • Cervical cancer
  • Cervix
  • Epigenetic
  • Epigenetics
  • Epithelial-mesenchymal transition
  • LIM homeobox
  • LMX-1A
  • Metastasis
  • Methylation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Liu, C. Y., Chao, T. K., Su, P. H., Lee, H. Y., Shih, Y. L., Su, H. Y., ... Lai, H. C. (2009). Characterization of LMX-1A as a metastasis suppressor in cervical cancer. Journal of Pathology, 219(2), 222-231. https://doi.org/10.1002/path.2589

Characterization of LMX-1A as a metastasis suppressor in cervical cancer. / Liu, Chin Yu; Chao, Tai Kuang; Su, Po Hsuan; Lee, Hsin Yi; Shih, Yu Lueng; Su, Her Young; Chu, Tang Yuan; Yu, Mu Hsien; Lin, Ya Wen; Lai, Hung Cheng.

In: Journal of Pathology, Vol. 219, No. 2, 10.2009, p. 222-231.

Research output: Contribution to journalArticle

Liu, CY, Chao, TK, Su, PH, Lee, HY, Shih, YL, Su, HY, Chu, TY, Yu, MH, Lin, YW & Lai, HC 2009, 'Characterization of LMX-1A as a metastasis suppressor in cervical cancer', Journal of Pathology, vol. 219, no. 2, pp. 222-231. https://doi.org/10.1002/path.2589
Liu, Chin Yu ; Chao, Tai Kuang ; Su, Po Hsuan ; Lee, Hsin Yi ; Shih, Yu Lueng ; Su, Her Young ; Chu, Tang Yuan ; Yu, Mu Hsien ; Lin, Ya Wen ; Lai, Hung Cheng. / Characterization of LMX-1A as a metastasis suppressor in cervical cancer. In: Journal of Pathology. 2009 ; Vol. 219, No. 2. pp. 222-231.
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abstract = "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 overexpressing 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.",
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