Neddylation pathway promotes myeloid-derived suppressor cell infiltration via NF-κB-mCXCL5 signaling in lung cancer.

Myeloid-derived suppressor cells (MDSCs), a population derived from immature myeloid progenitors, are present in the tumors of patients and highly protumorigenic. However, the molecular mechanisms regulating MDSC infiltration remain unclear. Neddylation pathway is overactivated in multiple cancers and has a significant role in tumor progression. We established a subcutaneous transplantation model of Lewis lung cancer in mice and showed that inactivation of neddylation pathway inhibits MDSC infiltration and impairs lung cancer growth. A high expression level of neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8) is positively correlated with MDSC infiltration in human lung adenocarcinomas (LUADs). Moreover, inactivation of neddylation pathway inhibits the expression of murine CXCL5 (mCXCL5; human homolog CXCL6, hCXCL6), an important cytokine implicated in MDSC recruitment. Mechanistically, inactivation of neddylation pathway inhibits activity of Cullin-RING ligase 1, a typical neddylation substrate, and induces accumulation of phosphorylated IκBα and subsequent blockage of NF-κB translocation, thus suppressing transcriptional activation of mCxcl5 or hCXCL6. Collectively, our data suggest that neddylation-NF-κB-mCXCL5 axis is involved in MDSC recruitment to the tumor sites and demonstrate that neddylation pathway is a good therapeutic target for patients with LUAD, particularly those receiving anti-MDSC therapy.

Pure shear deformation and its induced mechanical responses in metallic glasses.

Shear is a basic deformation mode governing yielding, plasticity and fracture in metallic solids. For amorphous metals, due to various constraints, little work is available in addressing directly shear deformation and shear-induced mechanical property changes which are vital to the mechanistic understanding of this new class of disordered materials. Here, by using a finite deformation theory, we examine the pure shear deformation in a bulk metallic glass in a large range of shear strains. With the continuum approach, we show systematically for the first time the detailed shear deformation behaviours, shear-induced normal stress and strain relations, softening in the elastic constants, volume dilatation and free energy change induced by the shear deformation. These results point to two major consequences from the shear deformation, one is the mechanical degradations and the other material degradation which is responsible for the changes in the mechanical properties of the disordered materials.