SerpinB3/B4: Mediators of Ras-driven inflammation and oncogenesis

Abstract

Mutant Ras is one of the most prevalent oncogenes in human cancers. The ability of oncogenic Ras to promote tumor growth in a cell intrinsic manner has been appreciated. In addition to hyperplasia, activated Ras controls cancer cell differentiation status marked by metaplasia, epithelial-mesenchymal transition, and acquisition of stem-cell traits. Over the last decade, the ability of mutant Ras to promote tumor development and progression in a non-cell autonomous manner has been unraveled. Through the up-regulation and secretion of various cytokines and chemokines, mutant Ras has been shown to directly contribute to malignancy by promoting basement membrane degradation and dysplasia, neovascularization, and suppression of anti-tumor immunity. However, the exact mechanism through which mutant Ras elicits the pro-inflammatory secretory response remains unknown. In 2 recent studies, we report squamous cell carcinoma antigens (SCCA) SerpinB3/SerpinB4 as novel pro-tumorigenic mediators downstream of mutant Ras via the activation of NF-κB and pro-inflammatory cytokine production.1,2