ZEB1 Promotes the Aggressive Characteristics of Pulmonary Sarcomatoid Carcinoma

To determine the role of Zinc finger E-box binding homeobox factor 1 (ZEB1) in pulmonary sarcomatoid carcinoma (PSC), we determined whether its expression in 40 PSC and 100 papillary lung carcinoma (Pap-LC) samples correlates. PSC patients with high ZEB1 had a significantly poorer prognosis when compared with Pap-LC; this was also the case for epithelial-to-mesenchymal transition (EMT) factor Slug, but not Snail or Twist1. A combined ZEB1-high and Slug-high scores appeared to be associated with the worst prognosis in PSC, suggesting that this metric may have great utility in predicting disease progression. ZEB1 was transcriptionally upregulated by the TGF-β1/Smad2 axis and ZEB1/Slug feedback loop, leading to repression of E-cadherin and induction of EMT/cancer stem cell (CSC) properties. Reduced ZEB1 expression due to ubiquitin-proteasomal degradation was associated with giant/senescent cell phenotypes. Consistent with this, ZEB1 expression was lowest in PSC samples with a high proportion of giant/senescent cell types, where prognosis was favorable. Increased expression of p21^waf1, p16^INK4A, and ubiquitin was concomitant with reduced ZEB1. Together, our findings reveal novel mechanistic insight into the establishment and maintenance of PSC phenotypes through ZEB1-dependent induction of EMT/CSC properties and suppression of senescence.