Exosomes with low miR-34c-3p expression promote invasion and migration of non-small cell lung cancer by upregulating integrinα2β1

Exosomes play critical roles in regulating various physiological and pathological processes,including immune stimulation,immune suppression,cardiovascular diseases,and cancers.Recent studies show that exosomes that transport specific microRNAs(miRNAs)are involved in tumor development.However,the molecular mechanism by which tumor invasion and migration are regulated by exosomes from non-small cell lung cancer(NSCLC)is not well understood.Here,we show that exosomes shuttling low levels of miR-34c-3p are involved in NSCLC progression.Our results showed that exosomes derived from NSCLC cells carrying low levels of miR-34c-3p could be transported into the cytoplasm of NSCLC cells and accelerate NSCLC invasion and migration by upregulating integrinα2β1.A luciferase assay revealed that integrinα2β1 was the direct target of miR-34c-3p,and overexpression of integrinα2β1 could promote the invasion and migration of NSCLC cells.The analysis of exosomes derived from clinical serum samples indicated that the expression of miR-34c-3p was significantly downregulated in exosomes from NSCLC patients compared with that of normal controls.A549-derived exosomes promoted NSCLC cells lung metastases in vivo.Exosomes shuttling low levels of miR-34c-3p were associated with the progression of NSCLC in vitro and in vivo.Our data demonstrate that exosomes shuttling low levels of miR-34c-3p can accelerate the invasion and migration of NSCLC by upregulating integrinα2β1.MiR-34c-3p can be a diagnostic and prognostic marker for NSCLC.High expression of integrinα2β1 is positively related to the migration and metastasis of NSCLC cells.

The key roles of cancer stem cell-derived extracellular vesicles

Cancer stem cells(CSCs),the subpopulation of cancer cells,have the capability of proliferation,self-renewal,and differentiation.The presence of CSCs is a key factor leading to tumor progression and metastasis.Extracellular vesicles(EVs)are nano-sized particles released by different kinds of cells and have the capacity to deliver certain cargoes,such as nucleic acids,proteins,and lipids,which have been recognized as a vital mediator in cell-to-cell communication.Recently,more and more studies have reported that EVs shed by CSCs make a significant contribution to tumor progression.CSCs-derived EVs are involved in tumor resistance,metastasis,angiogenesis,as well as the maintenance of sternness phenotype and tumor immunosuppression microenvironment.Here,we summarized the molecular mechanism by which CSCs-derived EVs in tumor progression.We believed that the fully understanding of the roles of CSCs-derived EVs in tumor development will definitely provide new ideas for CSCs-based therapeutic strategies.

PD0325901, an ERK inhibitor, enhances the efficacy of PD-1 inhibitor in non-small cell lung carcinoma

ERK pathway regulated the programmed death ligand-1(PD-L1)expression which was linked to the response of programmed death-1(PD-1)/PD-L1 blockade therapy.So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy.In this study,PD0325901,an oral potent ERK inhibitor,strongly enhanced the efficacy of PD-1 antibody in vitro and in vivo models in non-small cell lung carcinoma(NSCLC)cells.Mechanistically,PD0325901 or shRNA-ERK1/2 significantly downregulated the PD-L1 expression in NSCLC cells and increased the CD3+T cells infiltration and functions in tumor tissue.There was a positive correlation between the p-ERK1/2 expression and PD-L1 expression in patients with NSCLC.And the patients with low p-ERK1/2 expression were observed a high response rate of PD-1/PD-L1 blockage therapy.Our results demonstrate that PD0325901,an ERK inhibitor,can enhance the efficacy of PD-1 blockage against NSCLC in vitro and in vivo models.And the combination of ERK inhibitor such as PD0325901 and PD-1/PD-L1 blockage is a promising regimen and encouraged to be further confirmed in the treatment of patients with NSCLC.