title: The homeoprotein DLX4 stimulates NF-κB activation and CD44-mediated tumor-mesothelial cell interactions in ovarian cancer.
abstract: Ovarian cancers often highly express inflammatory cytokines and form implants throughout the peritoneal cavity. However, the mechanisms that drive inflammatory signaling and peritoneal metastasis of ovarian cancer are poorly understood. We previously identified that high expression of DLX4, a transcription factor encoded by a homeobox gene, is associated with reduced survival of ovarian cancer patients. In this study, we identified that DLX4 stimulates attachment of ovarian tumor cells to peritoneal mesothelial cells in vitro and increases the numbers of peritoneal implants in xenograft models. DLX4 induced expression of the cell surface molecule CD44 in ovarian tumor cells, and inhibition of CD44 abrogated the ability of DLX4 to stimulate tumor-mesothelial cell interactions. The induction of CD44 by DLX4 was attributed to increased activity of NF-κB that was stimulated by the inflammatory cytokine IL-1β, a transcriptional target of DLX4. The stimulatory effects of DLX4 on CD44 levels and tumor-mesothelial cell interactions were abrogated when IL-1β or NF-κB was inhibited in tumor cells. Furthermore, DLX4 expression levels strongly correlated with NF-κB activation and disease stage in clinical specimens of ovarian cancer. Collectively, these findings indicate that DLX4 induces CD44 by stimulating IL-1β-mediated NF-κB activity, thereby promoting peritoneal metastasis of ovarian cancer.
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dhwani
authors.initials: D
authors.lastname: Haria
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bon Quy
authors.initials: BQ
authors.lastname: Trinh
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Ko
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Barengo
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: hnaora@mdanderson.org.
authors.forename: Honami
authors.initials: H
authors.lastname: Naora
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C105304:DLX4 protein, human; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D053583:Interleukin-1beta; D016328:NF-kappa B; D014157:Transcription Factors