Mutant p53 regulates Survivin to foster lung metastasis

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers worldwide and evolves often to lung metastasis. <i>P53^R175H</i> (homologous to <i>Trp53</i>^<i>R172H</i> in mice) is a common hot spot mutation. How metastasis is regulated by p53^R175H in ESCC remains to be investigated. To investigate p53^R175H-mediated molecular mechanisms, we used a carcinogen-induced approach in <i>Trp53^R172H/-</i> mice to model ESCC. In the primary <i>Trp53^R172H/-</i> tumor cell lines, we depleted Trp53^R172H (shTrp53) and observed a marked reduction in cell invasion in vitro and lung metastasis burden in a tail-vein injection model in comparing isogenic cells (shCtrl). Furthermore, we performed bulk RNA-seq to compare gene expression profiles of metastatic and primary shCtrl and shTrp53 cells. We identified the YAP-<i>BIRC5</i> axis as a potential mediator of <i>Trp53</i>^<i>R172H</i> -mediated metastasis. We demonstrate that expression of Survivin, an antiapoptotic protein encoded by <i>BIRC5</i>, increases in the presence of Trp53^R172H Furthermore, depletion of Survivin specifically decreases Trp53^R172H-driven lung metastasis. Mechanistically, Trp53^R172H but not wild-type Trp53, binds with YAP in ESCC cells, suggesting their cooperation to induce Survivin expression. Furthermore, Survivin high expression level is associated with increased metastasis in several GI cancers. Taken together, this study unravels new insights into how mutant p53 mediates metastasis.