Microenvironment-induced TIMP2 loss by cancer-secreted exosomal miR-4443 promotes liver metastasis of breast cancer

We aimed to investigate the role of exosomal miR-4443 in metastasis of breast cancer (BCa). In vitro wound-healing assay and transwell invasion assay were used to investigate effect of miR-4443 on BCa cells. Animal experiments were performed to confirm its effects in vivo. miR-4443 promotes the metastasis of BCa cells through downregulating tissue inhibitors of metalloproteinase 2 (TIMP2) and upregulating matrix metalloproteinases (MMPs). Highly invasive BCa cells have a higher expression of miR-4443 in both cells and exosomes. The exosomes derived from highly invasive BCa cells mainly gather in the primary tumor and liver. In vivo, overexpression of miR-4443 in noninvasive BCa cells induces liver metastasis, accompanied with downregulated TIMP2, and upregulated MMP-2 in both the primary tumor and liver. When we armed MCF-10A exosomes with miR-4443 inhibitors to treat mice bearing high-miR-4443 tumors, exosomes accumulated in the primary tumor, and liver following the upregulation of TIMP2 and downregulation of MMP2, and the metastasis was inhibited. Highly invasive BCa cells destroy natural barriers against metastasis by delivering exosomal miR-4443 to stromal cells of the primary tumor and impairing TIMP2, consequently activating MMP; circulating exosomal miR-4443 might promote BCa cells lodging in future metastatic sites through the similar mechanisms.     

SKIL facilitates tumorigenesis and immune escape of NSCLC via upregulating TAZ/autophagy axis

Immune escape is an important mechanism in tumorigenesis. The aim of this study was to investigate roles of SKIL in tumorigenesis and immune escape of non-small-cell lung cancer (NSCLC). SKIL expression levels in NSCLC cell line, clinical sample, and adjacent normal tissue were measured by quantitative PCR, western blot, or immunohistochemistry. Lentivirus was used to overexpress/silence SKIL or TAZ expression. Malignant phenotypes of NSCLC cells were evaluated by colony formation, transwell, and MTT assays, and in xenograft mice model. Syngeneic mice model and flow cytometry were used to evaluate T cell infiltration. Quantitative PCR and western blot were applied to evaluate relevant mRNA and protein levels, respectively. Co-immunoprecipitation was applied to unveil the interaction between SKIL and TAZ. SKIL expression was higher in NSCLC tissue compared to adjacent normal tissue. Silencing of SKIL inhibited malignant phenotypes of NSCLC cells and promoted T cell infiltration. SKIL-knockdown inhibited autophagy and activated the STING pathway in NSCLC cells through down-regulation of TAZ. Silencing of TAZ cancelled the effects of SKIL overexpression on malignant phenotypes and autophagy of NSCLC cells. Inhibition of autophagy reversed the effects of SKIL/TAZ overexpression on the STING pathway. In conclusion, SKIL promoted tumorigenesis and immune escape of NSCLC cells through upregulation of TAZ/autophagy axis and inhibition on downstream STING pathway.Subject terms: Immunology, Cancer     

Four New Diterpenoid Alkaloids from The Roots of Aconitum coreanum

Four new hetisine‐type C₂₀‐diterpenoid alkaloids, named as coreanines A–D ( 1 – 4 ), were isolated from the roots of Aconitum coreanum, together with thirteen known alkaloids ( 5 – 17 ). Their structures were elucidated by extensive spectroscopic methods including IR, HR‐ESI‐MS and NMR techniques. All the isolated compounds were screened for the acetylcholinesterase (AChE) inhibitory effects, and none of them showed considerable inhibitory activity.