Delta-like ligand 4 (DLL4) messenger RNA (DLL4 mRNA)

Delta-like ligand 4 (DLL4) messenger RNA (mRNA) is the transcript encoding the DLL4 protein, a critical transmembrane ligand in the Notch signaling pathway. Primarily expressed in vascular endothelial cells, DLL4 is essential for regulating angiogenic sprouting and vessel maturation by activating Notch1 and Notch4 receptors on neighboring cells. This interaction acts as a critical "brake" on vascular growth, ensuring the development of a functional and organized blood vessel network. Beyond its role in angiogenesis, DLL4 is involved in cell fate determination and T-cell development in the thymus. In many cancers, DLL4 mRNA is significantly overexpressed in the tumor vasculature, where it promotes a functional but abnormal vessel network that supports tumor progression and resistance to anti-VEGF therapies. Targeting DLL4 mRNA using RNA interference (siRNA) or antisense oligonucleotides (ASOs) aims to silence the expression of the DLL4 protein at the pre-translational level, thereby disrupting the Notch-mediated regulation of angiogenesis. This approach induces "non-productive" vessel sprouting, which starves the tumor of nutrients and oxygen. While most clinical-stage drugs like Demcizumab target the DLL4 protein, mRNA-targeted strategies offer a method to prevent ligand production entirely. However, therapeutic challenges include managing systemic side effects such as hypertension and gastrointestinal toxicity, which are common to Notch pathway inhibition.

Other names

Delta-like protein 4 mRNADLL4 transcriptDelta-like 4 mRNAhDLL4 mRNADelta-like canonical Notch ligand 4 mRNA

RNA interference (siRNA-mediated degradation) or antisense-mediated translational inhibition.