Cancer tissues consist of cancer cells, surrounding stromal cells and the extracellular matrix. Cancer‐associated fibroblasts ( CAF ) are one of the key components of stromal cells. CAF have a great impact on the behavior of cancer cells, including proliferation, invasion, metastasis and chemoresistance in many ways. However, the underlying mechanism had not been fully elucidated. In this study, we investigated the role of CAF in cisplatin resistance of lung cancer cells. By using conditioned medium from CAF ( CAF ‐ CM ), we found that CAF decreased the sensitivity of lung cancer cells to cisplatin. RNA sequencing results showed that CAF expressed a higher level of Annexin A3 ( ANXA 3) than normal fibroblasts ( NF ), and CAF ‐ CM incubation increased the ANXA 3 level in lung cancer cells. Overexpression of ANXA 3 in lung cancer cells increased cisplatin resistance and activated c‐jun N‐terminal kinase ( JNK ), whereas knockdown of ANXA 3 increased cisplatin sensitivity. Further study showed that CAF ‐ CM enhanced cisplatin resistance by inhibiting cisplatin‐induced apoptosis, determined by repression of caspase‐3 and caspase‐8, through activation of the ANXA 3/ JNK pathway. Conversely, suppression of JNK activation by specific inhibitor retarded the effect of CAF ‐ CM and ANXA 3 on cisplatin sensitivity. Taken together, our study demonstrated that CAF potentiated chemoresistance of lung cancer cells through a novel ANXA 3/ JNK pathway both in vitro and in vivo, suggesting ANXA 3 could be a potential therapeutic target for the treatment of chemoresistant cancer.

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In this study, we used a systems vaccinology approach to identify temporal changes in immune response signatures to the yellow fever (YF)-17D vaccine, with the aim of comprehensively characterizing immune responses associated with protective immunity. We conducted a cohort study in which 21 healthy subjects in China were administered one dose of the YF-17D vaccine; PBMCs were collected at 0 h and then at 4 h and days 1, 2, 3, 5, 7, 14, 28, 84, and 168 postvaccination, and analyzed by transcriptional profiling and immunological assays. At 4 h postvaccination, genes associated with innate cell differentiation and cytokine pathways were dramatically downregulated, whereas receptor genes were upregulated, compared with their baseline levels at 0 h. Immune response pathways were primarily upregulated on days 5 and 7, accompanied by the upregulation of the transcriptional factors JUP, STAT1, and EIF2AK2. We also observed robust activation of innate immunity within 2 d postvaccination and a durable adaptive response, as assessed by transcriptional profiling. Coexpression network analysis indicated that lysosome activity and lymphocyte proliferation were associated with dendritic cell (DC) and CD4 T cell responses; FGL2, NFAM1, CCR1, and TNFSF13B were involved in these associations. Moreover, individuals who were baseline-seropositive for Abs against another flavivirus exhibited significantly impaired DC, NK cell, and T cell function in response to YF-17D vaccination. Overall, our findings indicate that YF-17D vaccination induces a prompt innate immune response and DC activation, a robust Ag-specific T cell response, and a persistent B cell/memory B cell response.

Phenethyl isothiocyanate (PEITC) is a natural compound abundant in cruciferous vegetables. PEITC possesses anti-tumor effect in various human malignances. Our previous study has shown that benzyl isothiocyanates (BITC) induce autophagy in lung cancer cells. However, whether autophagy play a role in the inhibitory effect of PEITC on lung cancer metastasis is unclear. In this study, we found that PEITC suppressed migration and invasion of lung cancer cells by regulating MMP2. It also induced autophagy, evidenced by the formation of acidic vesicular organelles (AVOs), the punctate pattern of LC3, the accumulation of LC3-II, and the expression of Beclin-1. Inhibition of autophagy by 3-MA and chloroquine (CQ) or knock down of Beclin-1 enhanced PEITC-caused metastasis inhibition. JAK2/STAT3 pathway was suppressed by PEITC, and further inhibited by 3-MA and CQ or Beclin-1 knock down, as a result of decreased expression of p-JAK2 and p-STAT3. Blocking JAK2/STAT3 pathway by inhibitor AG490 and Stattic suppressed cell migration and decreased the expression of MMP2, MMP9, Twist, and c-Myc. Further in vivo study showed that PEITC inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3 pathway, and inhibitor CQ enhanced this effect. Taken together, our results demonstrate that PEITC inhibits metastasis potential of lung cancer cells, and induces autophagy. The autophagy induced by PEITC preserves metastasis potential of lung cancer cells, via activation of JAK2/STAT3 pathway. Inhibition of autophagy enhanced the inhibitory effect of PEITC on metastasis potential of lung cancer cells. Our finding suggests that targeting autophagy could be a promising strategy for anti-metastasis therapies.

Su(var)3-9, enhancer of zeste, Trithorax] domaincontaining protein 7 (SETd7) is a protein lysine methyltransferase that methylates both histone H3K4 and non-histone proteins, such as transcription factors. The methylation on proteins alters their activity and affects a series of biological processes. Recent studies have demonstrated that SETd7 contributes to tumor progression and may play different roles in tumor development. However, the effect of SETd7 on lung cancer cell migration and invasion has not been fully elucidated. The present study demonstrated that the expression of SETD7 was significantly downregulated in lung cancer tissues in comparison with that in matched non-cancer tissues, and lung cancer cell lines also exhibited lower SETd7 levels compared with normal human bronchial epithelial cells. Overexpression of SETd7 inhibited the migration and invasion of lung cancer cells, whereas decreased SETd7 expression promoted cell migration and invasion. Further study revealed that SETd7 regulated the expression of the metastasis-related genes metalloproteinase 2, Twist1 and vascular endothelial growth factor. Furthermore, SETd7 knockdown activated the Janus kinase 2/signal transducer and activator of transcription 3 (STAT3) signaling pathway and enhanced lung cancer cell migration, whereas the STAT3-specific inhibitor Stattic abrogated the effect of SETd7 on cell migration. Taken together, these data indicated that SETd7 acts as a tumor suppressor, and the reduced expression of SETd7 may contribute to lung cancer progression. The findings of the present study suggest that SETd7 may be a novel candidate for the treatment of metastatic lung cancer.