Exosome-transmitted S100A4 induces immunosuppression and non-small cell lung cancer development by activating STAT3.

Non-small cell lung cancer (NSCLC) is the primary reason of tumor morbidity and mortality worldwide. We aimed to study the transfer process of S100A4 between cells and whether it affected NSCLC development by affecting STAT3 expression. First, S100A4 expression in NSCLC cells was measured. The exosomes in MRC-5, A549, and H1299 cells were isolated and identified. We constructed si-S100A4 and si-PD-L1 to transfect A549 cells and oe-S100A4 to transfect H1299 cells, and tested the transfection efficiency. Cell function experiments were performed to assess cell proliferation, clone number, apoptosis, cell cycle, migration, and invasion abilities. In addition, ChIP was applied to determine the targeting relationship between S100A4 and STAT3. Next, we explored NSCLC cell-derived exosomes role in NSCLC progress by transmitting S100A4. Finally, we verified the function of exosome-transmitted S100A4 in NSCLC in vivo. High expression of S100A4 was secreted by exosomes. After knocking down S100A4, cell proliferation ability was decreased, clones number was decreased, apoptosis was increased, G1 phase was increased, S phase was repressed, and migration and invasion abilities were also decreased. ChIP validated STAT3 and PD-L1 interaction. After knocking down S100A4, PD-L1 expression was decreased, while ov-STAT3 reversed the effect of S100A4 on PD-L1 expression. Meanwhile, S100A4 inhibited T-cell immune activity by activating STAT3. In addition, knockdown of PD-L1 inhibited cell proliferation, migration, and invasion. NSCLC cell-derived exosomes promoted cancer progression by transmitting S100A4 to activate STAT3 pathway. Finally, in vivo experiments further verified that exosome-transmitted S100A4 promoted NSCLC progression. Exosome-transmitted S100A4 induces immunosuppression and the development of NSCLC by activating STAT3.

[Effect of lumbrokinase on patients with acute and moderate risk pulmonary thromboembolism].

OBJECTIVE: To explore the clinical efficacy and safety of lumbrokinase in the treatment of acute and moderate risk pulmonary thromboembolism.
 Methods: The clinical data of 60 patients with acute and moderate risk pulmonary thromboembolism, who were collected from January 2010 to October 2015 in Hunan Provincial People's Hospital, were retrospectively analyzed. According to the different treatments, 60 patients were randomly divided into a lumbrokinase group (lumbrokinase in combination with low molecular heparin and sequential warfarin, n=30) and a control group (low molecular heparin and sequential warfarin, n=30). The clinical efficacy and safety were compared between the two groups.
 Results: Compared with the control group, maximum short axis, ratio of right and left ventricles, systolic pulmonary artery pressure, and the main pulmonary artery diameter in the lumbrokinase group were significant changed after the treatment for 10, 20 and 30 d. NT-proBNP level in the lumbrokinase group after the treatment for 10, 20 and 30 d was significantly reduced than that in the the control group (P<0.05). However, the value of PO2 significantly increased after 10, 20 and 30 d, and there was no significant difference between 20 d and 30 d (P>0.05). D-dimer in the two groups was obviously increased after treatment for 10 d, but it was significantly reduced after treatment for 20 d or 30 d (P<0.05). The clinical efficacy of the lumbrokinase group was better than that in the control group, with significant difference (P<0.05).
 Conclusion: Combination of lumbrokinase with low molecular heparin and sequential warfarin is a safe and efficient strategy in treating the patients with acute and moderate risk pulmonary thromboembolism. It is worthy of clinical popularization and application.