Abstract
Cancer is among the leading causes of death in the USA and worldwide. Solid tumors require the formation of new blood vessels (angiogenesis) for their growth. The endothelium plays a crucial role in angiogenesis and tumor progression. Hypoxic stress generated by tumors can activate stress kinases such as mixed lineage kinases (MLKs). Publicly available datasets on lung adenocarcinoma, along with our experimental findings, indicate that MLK2 and MLK3 are expressed in human lung tumors. In this study, using three distinct mouse models of tumor development, we demonstrated that MLK2 (MAP3K10) and MLK3 (MAP3K11) are essential for tumor growth and angiogenesis. Furthermore, MLK2 and MLK3 are highly expressed in the endothelium and are necessary for endothelial proliferation, migration, and angiogenesis. In the endothelium, MLKs regulate the expression of angiogenic growth factors and metalloproteinases, including Pgf, Vegfa, Angptl4, Adam8, and Mmp9. Additionally, the MLK family of kinases acts through the long noncoding RNA (lncRNA) H19 to control the expression of these pro-angiogenic factors in the endothelium. Collectively, these findings suggest that the MLK-H19 axis coordinates endothelial function, angiogenesis, and tumor growth.