Background/Aims: The malignant biological behavior of gastric cancer(GC) is not only determined by cancer cells alone, but also closely regulated by the microenvironment. Fibroblasts represent a large proportion of the components in the tumor microenvironment, and they promote the development of disease. Currently, accumulating evidence suggests that exosomes can function as intercellular transport systems to relay their contents, especially microRNAs(miRNAs). Methods: First, we detected the highly-expressed level of miR-27a in exosomes isolated from gastric cancer cells by qRT-PCR. MiR-27a –over-expressed models in vitro and in vivo were established to investigate the transformation of cancer-associated fibroblasts observed by Western blotting, and the malignant behavior of gastric cancer cells using the methods CCK8 and Transwell. Moreover, the downregulation of CSRP2 in fibroblasts was used to evaluate the promotion of malignancy of gastric cancer using the methods CCK8 and Transwell. Results: In this study, we found a marked high level of miR-27a in exosomes derived from GC cells. miR-27a was found to function an oncogene that not only induced the reprogramming of fibroblasts into cancer-associated fibroblasts(CAFs), but also promoted the proliferation, motility and metastasis of cancer cells in vitro and in vivo. Conversely, CAFs with over-expression of miR-27a could pleiotropically increase the malignant behavior of the GC cells. For the first time, we revealed that CSRP2 is a downstream target of miR-27a. CSRP2 downregulation could increase the proliferation and motility of GC cells. Conclusion: Thus, this report indicates that miR-27a in exosomes derived from GC cells has a crucial impact on the microenvironment and may be used as a potential therapeutic target in the treatment of GC

Loss of CD20 is a major obstacle for the retreatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL) with Rituximab-associated regimens. Histone deacetylation causes gene silencing and inhibits CD20 expression. Chidamide is a novel inhibitor for histone deacetylases (HDACs). We hypothesize that Chidamide could overcome Rituximabmediated down-regulation of CD20 and facilitate Rituximab-induced killing. In this study, we determine the mechanism of synergy of Chidamide with Rituximab in DLBCL using in vitro and in vivo models. We found that the levels of CD20 protein surface expression on five DLBCL cell lines were significantly and positively correlated with the sensitivities of cells to Rituximab. Treatment with Rituximab significantly reduced CD20 surface expression at the protein levels. RNA sequencing showed that Chidamide significantly increased expression of more than 2000 transcriptomes in DLBCL cells, around 1000 transcriptomes belong to the cell membrane and cell periphery pathways, including MS4A1. Chidamide significantly increased CD20 surface expression in DLBCL cell lines. Combination with Chidamide significantly synergized Rituximab-induced cell death in vitro and significantly inhibited tumour growth in DLBCL-bearing xenograft mice. A patient with relapsed/refractory DLBCL achieved a complete response after three cycles combined treatment with Chidamide and Rituximab. In conclusion, our data demonstrate for the first time that inhibition of HDACs by Chidamide significantly enhanced Rituximab-induced tumour growth inhibition in vitro and in vivo. We propose that CD20 surface expression should be used clinically to evaluate treatment response in patients with DLBCL. Chidamide is a promising sensitizer for the retreatment of DLBCL with Rituximab.

High mobility group box 1 (HMGB1) protein in the tumor microenvironment actively contributes to tumor progression but its role in diffuse large B-cell lymphoma (DLBCL) is unknown. The aim of this study was to determine the mechanism by which HMGB1 promotes tumor growth in DLBCL and whether blockade of HMGB1 signaling pathway could inhibit tumorigenesis. We report that HMGB1 promotes proliferation of DLBCL cells by activation of AKT, extracellular signal-regulated kinases 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3) and SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase (Src). Ethyl pyruvate (EP), an anti-inflammatory agent, inhibits HMGB1 active release from DLBCL cells and significantly inhibited proliferation of DLBCL cells in vitro. Treatment with EP significantly prevented and inhibited tumor growth in vivo and prolonged DLBCL-bearing mice survival. EP significantly downregulated HMGB1 expression and phosphorylation of Src and ERK1/2 in mice lymphoma tissue. EP induced accumulation of the cell cycle inhibitor p27 but downregulated expression of cyclin-dependent kinase 2 (CDK2). Increased nuclear translocation of p27 interacted with CDK2 and cyclin A, which led to blockade of cell cycle progression at the G1 to S phase transition. In conclusion, we demonstrated for the first time that blockade of HMGB1-mediated signaling pathway by EP effectively inhibited DLBCL tumorigenesis and disease progression.