ACVR1C/SMAD2 signaling promotes invasion and growth in retinoblastoma.

摘要: Retinoblastoma is the most common intraocular cancer in children. While primary tumor can often be treated by local or systemic chemotherapy, metastatic dissemination generally resistant to therapy and remains a leading cause of pediatric death much world. In order identify new therapeutic targets aggressive tumors, we sequenced RNA transcripts five snap frozen retinoblastomas which invaded optic nerve did not. A three-fold increase was noted mRNA levels ACVR1C/ALK7, type I receptor TGF-β family, invasive retinoblastomas, while downregulation DACT2 LEFTY2, negative modulators ACVR1C signaling, observed tumors. two- also found WERI Rb1 Y79 cells as compared non-invasive vitro. Transcripts its ligands (Nodal, Activin A/B, GDF3) were expressed six retinoblastoma lines, evidence downstream SMAD2 signaling present all these lines. Pharmacological inhibition using SB505124, genetic shRNA potently suppressed invasion, growth, survival, reduced protein mesenchymal markers ZEB1 Snail. The inhibitory effects on proliferation recapitulated knocking down SMAD2, but not SMAD3. Finally, an orthotopic zebrafish model retinoblastoma, 55% decrease spread (p = 0.0026) when larvae with 3 µM DMSO. Similarly, knockdown injected resulted 54% reduction eye scrambled control (p = 0.0005). Our data support role for ACVR1C/SMAD2 pathway promoting invasion growth retinoblastoma.