Background Our previous report demonstrated that genetic ablation of miR-301a reduces Kras -driven lung tumorigenesis in mice. However, the impact of miR-301a on host anti-tumor immunity remains unexplored. Here we assessed the underlying molecular mechanisms of miR-301a in the tumor microenvironment. Methods The differentially expressed genes were identified by using deep sequencing. The immune cell counts, and cytokines expression were analyzed by realtime PCR, immunohistochemistry and flow cytometry. The role of miR-301a/Runx3 in lung tumor was evaluated on cell growth, migration and invasion. The function of miR-301a/Runx3 in regulating tumor microenvironment and tumor metastasis were evaluated in Kras transgenic mice and B16/LLC1 syngeneic xenografts tumor models. Results In this work, we identified 1166 up-regulated and 475 down-regulated differentially expressed genes in lung tumor tissues between Kras LA2 and miR-301a −/− ; Kras LA2 mice. Immune response and cell cycle were major pathways involved in the protective role of miR-301a deletion in lung tumorigenesis. Overexpression of the miR-301a target, Runx3, was an early event identified in miR-301a −/− ; Kras LA2 mice compared to WT-Kras LA2 mice. We found that miR-301a deletion enhanced CD8 + T cell accumulation and IFN-γ production in the tumor microenvironment and mediated antitumor immunity. Further studies revealed that miR-301a deficiency in the tumor microenvironment effectively reduced tumor metastasis by elevating Runx3 and recruiting CD8 + T cells, whereas miR-301a knockdown in tumor cells themselves restrained cell migration by elevating Runx3 expression. Conclusions Our findings further underscore that miR-301a facilitates tumor microenvironment antitumor immunity by Runx3 suppression in lung tumorigenesis. Electronic supplementary material The online version of this article (10.1186/s12943-019-1024-0) contains supplementary material, which is available to authorized users.

Arsenic is a well-known of human carcinogen and miR-301a is an oncogenic microRNA, which links to oncogenesis, however, little is understood about its contribution to arsenic-induced cellular transformation and tumorigenesis. Here, we investigated the role of miR-301a during arsenic-induced cellular transformation and tumor formation. miR-301a was found to be upregulated during arsenic-induced BEAS-2B transformation and the overexpression of miR-301a was dependent on IL-6/STAT3 signaling. Inhibition of miR-301a leads to reduction of cell proliferation, colony formation and cell migration. By using dual luciferase assay, SMAD4 was confirmed to be a direct target of miR-301a in BEAS-2B cells and upregulation of SMAD4 is involved the restraining cell growth and migration. In addition, reducing of miR-301a expression enhances doxorubicin-induced cellular apoptosis of transformed BEAS-2B through up-regulating SMAD4. Furthermore, we demonstrated that downregulation of miR-301a in BEAS-2B attenuates tumor growth in the xenograft model by targeting SMAD4. Of note, the level of miR-301a expression correlated inversely with SMAD4 expression in clinical specimens of human lung cancer. Our findings ascertain that miR-301a is an oncogenic miRNA, which targets SMAD4 to establish an essential mechanism for arsenic-induced carcinogenesis, IL-6/STAT3/miR-301a/SMAD4 signaling pathways.

Background/Aims: Our previous study demonstrated that a deficiency of microRNA 21 (miR-21) protects mice from acute pancreatitis, yet the underlying molecular networks associated with miR-21 in pancreatitis and pancreatitis-associated lung injury remain unexplored. Methods: We used next generation sequencing to analyze gene expression profiles of pancreatic tissues from wild-type (WT) and miR-21 knockout (KO) mice treated with caerulein by using a 1-day treatment protocol. The Database for Annotation, Visualization, and Integrated Discovery gene annotation tool and Ingenuity Pathway Analysis were used to analyze the molecular pathways, while quantitative real-time PCR, western blotting, and immunohistochemistry were used to explore the molecular mechanisms. Results: We identified 152 differentially expressed genes (DEGs) in pancreata between WT and KO mice treated with caerulein. Cellular biogenesis and metabolism were the major pathways affected between WT and KO mice, whereas cell death and inflammatory response discriminated between WT and KO mice under acute pancreatitis. We validated 16 DEGs, consisting of 6 upregulated genes and 10 downregulated genes, involved in pancreatic injury. In particular, the upregulation of Pias3 and downregulation of Hmgb1 in KO pancreata coincided with a reduced severity of pancreatitis. In addition, we found Hmgb1 stimulation resulted in the overexpression of miR-21 in peripheral blood mononuclear cells, and deletion of miR-21 led to a reduction of caerulein-induced acute pancreatitis-associated lung injury by repressing Hmgb1 expression. Conclusion: Our data support the hypothesis that miR-21 modulates the inflammatory response during acute pancreatitis through the upregulation of Pias3 and downregulation of Hmgb1. Our findings further underscore a role for miR-21 in the promotion of acute pancreatitis.