O33. STAT signaling in renal progenitor differentiation and tumorigenesis

Abstract

Listen

Translate article

While originally implicated in inflammatory and immune processes, it is now apparent that canonical STAT signaling drives a variety of fundamental cellular processes, including stem cell renewal, cell proliferation, migration, and progenitor differentiation. Furthermore, STATs are often constitutively activated/phosphorylated in an array of hematologic and solid neoplasms. In the developing kidney, STATs 1 and 3 are already phosphorylated in cortical progenitors at the earliest stages of rudiment formation, while most other STAT family members appear at later stages of nephrogenesis. Functionally, STAT3 activation is associated with the conversion of metanephric mesenchyme to form the epithelia of the nephron, whereas STAT1 activation stimulates progenitor proliferation, upregulates the expression of survival/anti-apoptotic factors such as Mcl-1, and inhbits mesenchymal-epithelial transition. Moreover, inactivation of STAT1 has the converse effect, accelerating tubule formation. The pediatric cancer, Wilms tumor, is derived from metanephric mesenchyme and caricatures the differentiation of this tissue. It is characterized by the expansion of a blastemal population that is inhibited in its ability to undergo mesenchymal–epithelial transition to form nephronic tubules. An examination of tumor tissues has revealed that STAT1, but not STAT3, is constitutively activated by phosphorylation of S727 in Wilms tumors. Furthermore, overexpression of an unphosphorylated mutant form, S727A-STAT1, or knockdown of endogenous STAT1 in renal tumor cells inhibits their anchorage-independent growth. Genomic expression profiling has determined that STAT1 activity in tumor cells is dependent in part on the up regulation of survival/anti-apoptotic factors, Mcl-1, Hsp-27, and Cux-1, and inhibition of STAT1 or these factors induces apoptosis in renal tumor cells. These findings demonstrate that both metanephric progenitors and renal tumor cells utilize a STAT1-dependent mechanism for growth/survival and possibly regulation of differentiation and suggest that inhibition of signaling by this transcription factor may provide an efficacious target for Wilms tumor therapy