Deregulation of the HOXA10 homeobox gene in endometrial carcinoma: role in epithelial-mesenchymal transition.
Homeobox genes encode transcription factors that control cell differentiation and play essential roles in developmental patterning. Increasing evidence indicates that many homeobox genes are aberrantly expressed in cancers, and that their deregulation significantly contributes to tumor progression. The homeobox gene HOXA10 controls uterine organogenesis during embryonic development and functional endometrial differentiation in the adult. We investigated whether HOXA10 expression is deregulated in endometrial carcinomas, and how counteracting this aberrant expression modifies tumor behavior. We found that down-regulation of HOXA10 expression in endometrial carcinomas strongly correlates with increased tumor grade and is associated with methylation of the HOXA10 promoter. Enforced expression of HOXA10 in endometrial carcinoma cells inhibited invasive behavior in vitro and tumor dissemination in nude mice. The inhibitory effect of HOXA10 on invasive behavior was attributable at least in part to the ability of HOXA10 to induce expression of the epithelial cell adhesion molecule E-cadherin by down-regulating expression of Snail, a repressor of E-cadherin gene transcription. These findings reveal a novel role for HOXA10 deregulation in the progression of endometrial carcinoma by promoting epithelial-mesenchymal transition.
Yoshida
Hiroyuki
H
Department of Molecular Therapeutics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Broaddus
Russell
R
Cheng
Wenjun
W
Xie
SuSu
S
Naora
Honami
H
D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000503:physiopathology; D002448:Cell Adhesion; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000502:physiology*; D018450:Disease Progression; D015536:Down-Regulation; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000503:physiopathology; D004848:Epithelium / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; D006801:Humans; D008648:Mesoderm / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D000080905:Homeobox A10 Proteins; D018398:Homeodomain Proteins; C069634:HOXA10 protein, human