Ano de Publicação: 2011
AUTORIA
Shizhang Ling1, Xiaofei Chang2, Luciana Schultz1, Thomas K. Lee1, Alcides Chaux1, Luigi
Marchionni1, George J. Netto1, David Sidransky2, and David M. Berman1
1Departments of Pathology and Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
2Department of Otolaryngology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA
RESUMO
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 HMG 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 demonstrated 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 to 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.