title: An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.
abstract: Like many carcinomas, urothelial carcinoma (UroCa) is associated with chronic injury. A better understanding of this association could inform improved strategies for preventing and treating this disease. We investigated the expression, regulation, and function of the transcriptional regulator SRY-related high-mobility group box 9 (Sox9) in urothelial development, injury repair, and cancer. In mouse bladders, Sox9 levels were high during periods of prenatal urothelial development and diminished with maturation after birth. In adult urothelial cells, Sox9 was quiescent but was rapidly induced by a variety of injuries, including exposure to the carcinogen cyclophosphamide, culture with hydrogen peroxide, and osmotic stress. Activation of extracellular signal-regulated kinases 1/2 (ERK1/2) was required for Sox9 induction in urothelial injury and resulted from activation of the epidermal growth factor receptor (Egfr) by several Egfr ligands that were dramatically induced by injury. In UroCa cell lines, SOX9 expression was constitutively upregulated and could be suppressed by EGFR or ERK1/2 blockade. Gene knockdown showed a role for SOX9 in cell migration and invasion. Accordingly, SOX9 protein levels were preferentially induced in invasive human UroCa tissue samples (n = 84) compared with noninvasive cancers (n = 56) or benign adjacent urothelium (n = 49). These results identify a novel, potentially oncogenic signaling axis linking urothelial injury to UroCa. Inhibiting this axis is feasible through a variety of pharmacologic approaches and may have clinical utility.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Shizhang
authors.initials: S
authors.lastname: Ling
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Chang
authors.forename: Luciana
authors.initials: L
authors.lastname: Schultz
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Lee
authors.forename: Alcides
authors.initials: A
authors.lastname: Chaux
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.forename: David M
authors.initials: DM
authors.lastname: Berman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D012038:Regeneration / Q000235:genetics; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014571:Urologic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019459:Urothelium / Q000254:growth & development / Q000378:metabolism / Q000473:pathology
chemical_list: D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases