The Mechanism of Pd-L1 Expression in Lung Cancer Cells Contributing to Metastasis, and Its Correlation with Tip60-Mediated with Epithelial-Mesenchymal Transition

Our study found overexpressing PD-L1 in lung adenocarcinoma CL1-0 cells with basal low PD-L1 expression would increase the expression of EMT markers, cell spindle-liked morphology, cellular migration and invasion ability via PDL1 exocytosis and then binding to its PD-1 receptor, located on the cell surface membrane. These results suggested that PD-L1 expression could directly promote lung cancer metastasis. Therefore, Pembrolizumab, not only kills cancer cells, but also suppresses tumor metastasis in lung cancer. (2019 AACR meeting Abstract) (revision to Lung Cancer; IF>4.0) Human HLTF and RAD51 recombinase can promote fork reversal formation in response to replication stress. However, how HLTF recruits RAD51 to stalled forks remains unclear. Here, we revealed that HLTF interacts with PARP1 and BARD1, and methyl methanesulfonate can enhance the interactions between HLTF, BARD1, and PARP1. The depletion of HLTF, PARP1, and BARD1 reduced the replication tracks after MMS treatment by the DNA fiber analysis, concomitantly with increasing numbers of stalled forks and collapse of forks resulting in double strain breaks (DSB). By combining 5-ethynyl-2'-deoxyuridine with proximity ligation assay, we revealed that the HLTF, BRCA1/BARD1/RAD51, and PARP1 proteins were recruited to stalled forks initially. However, by the time when stalled forks start to collapse, HLTF starts to dissociate from stalled forks, whereas BRCA1/BARD1/RAD51, and PARP1 accumulate more at collapsed forks. Our results revealed that these proteins recruited to stalled forks are dynamic processes, not only participating in template-switching, but also homologous recombination repair at collapsed forks. So we concluded that we may check HLTF gene status before we use the PARP1 inhibitor to gain maximal efficacy in cancer therapy. (Oncogenesis, revision, completed, IF>6.0) Besides, Hypoxia frequently occurrs in tumor microenvironment, and so we have designed GSH-driven PAHSS-PLGA nanoparticles to overcome drug resistance in hypoxic microenvironment. We have demonstrated when the nanoparticle were uptaken by the cancer cells, intracellular GSH can make the nanoparticle easy to be broken to release their payload. Finally, the cancer cells become easy to get apoptosis. The results were published in Pharmaceutics 2020, 12 (8), 0778.