Delivery of SIRT1 by cancer-associated adipocyte-derived extracellular vesicles regulates immune response and tumorigenesis of ovarian cancer cells.

PURPOSE: This study intends to investigate the possible molecular mechanism of immune response and tumorigenesis in ovarian cancer cells, mediated by sirtuin 1 (SIRT1)-containing extracellular vesicles (EVs) derived from cancer-associated adipocytes (CAAs) (CAA-EVs). METHODS: Differentially expressed genes in EVs from CAAs were screened by RNA transcriptome sequencing, and the downstream pathway was predicted in silico. The binding between SIRT1 and CD24 was investigated by luciferase activity and ChIP-PCR assays. EVs were extracted from human ovarian cancer tissue-isolated CAAs, and the internalization of CCA-EVs by ovarian cancer cells was characterized. The ovarian cancer cell line was injected into mice to establish an animal model. Flow cytometry was performed to analyze the proportions of M1 and M2 macrophages, CD8+ T, T-reg, and CD4+ T cells. TUNEL staining was used to detect cell apoptosis in the mouse tumor tissues. ELISA detection was performed on immune-related factors in the serum of mice. RESULTS: CAA-EVs could deliver SIRT1 to ovarian cancer cells, thereby affecting the immune response of ovarian cancer cells in vitro and promoting tumorigenesis in vivo. SIRT1 could transcriptionally activate the expression of CD24, and CD24 could up-regulate Siglec-10 expression. CAA-EVs-SIRT1 activated the CD24/Siglec-10 axis and promoted CD8+ T cell apoptosis, thereby promoting tumorigenesis in mice. CONCLUSION: CAA-EVs-mediated transfer of SIRT1 regulates the CD24/Siglec-10 axis to curb immune response and promote tumorigenesis of ovarian cancer cells.

LINC01119 encapsulated by cancer-associated adipocytes-derived exosomes promotes M2 polarization of macrophages to induce immune escape in ovarian cancer in a 3D co-culture cell-based model.

INTRODUCTION: In the present study, we sought to clarify the role of LINC01119 delivered by cancer-associated adipocytes (CAAs)-derived exosomes (CAA-Exo) and its mechanistic actions in ovarian cancer (OC). MATERIALS AND METHODS: The expression of LINC01119 was determined in OC, and the relationship between LINC01119 expression and the prognosis of OC patients was analyzed. Besides, 3D co-culture cell models were constructed using green fluorescent protein-labeled OC cells and red fluorescent protein-labeled mature adipocytes. Mature adipocytes were co-cultured with OC cells to induce CAA. Macrophages treated with CAA-Exo were co-cultured with SKOV3 cells following ectopic expression and depletion experiments of LINC01119 and SOCS5 to detect M2 polarization of macrophages, PD-L1 level, proliferation of CD3+ T cells, and cytotoxicity of T cells to SKOV3 cells. RESULTS: LINC01119 was elevated in the plasma Exo of OC patients, which was related to shorter overall survival in OC patients. LINC01119 expression was increased in CAA-Exo, which could upregulate SOCS5 in OC. Finally, CAA-Exo carrying LINC01119 induced M2 polarization of macrophages to promote immune escape in OC, as evidenced by inhibited CD3+ T cell proliferation, increased PD-L1 level, and attenuated T cell toxicity to SKOV3 cells. CONCLUSION: In conclusion, the key findings of the current study demonstrated the promoting effects of CAA-Exo containing LINC01119 mediating SOCS5 on M2 polarization of macrophages and immune escape in OC.

Dynamics of environmental policy and firm innovation: Asymmetric effects in Canada's oil and gas industries.

Considering that Canada joined and then withdrew from the Kyoto Protocol, we assess the impact of the dynamics of Canada's environmental policy on the general innovation and environmental innovation of oil and gas firms. This study compensates for the shortcomings of the Porter hypothesis, which features no discussion of the influence of a loosened environmental policy on innovation. We highlight that the quantity and quality of innovation can be measured using the numbers of patents and citations of patents as proxy variables. We find that the dynamics of Canada's environmental policy have an asymmetric impact on oil and gas firms' innovation; strict policy promotes firm innovation and loose regulation reduces firm innovation, with the positive effect of strict policy being stronger than the negative effect of loose policy. In addition, environmental policy has a strong impact on environmental innovation. A loosened environmental policy increases the number of environmental patents but reduces the number of citations of environmental patents.

Infiltrations of plasma cells in synovium are highly associated with synovial fluid levels of APRIL in inflamed peripheral joints of rheumatoid arthritis.

Infiltration of plasma cells can be a histopathological hallmark of articular synovium with rheumatoid arthritis (RA). A proliferation-inducing ligand (APRIL) may have key roles in homeostasis and development of B cells, and the differentiation of B cells into plasma cells. This study was designed to explore the relationships between the infiltrations of plasma cells in synovium and the synovial fluid levels of APRIL in inflamed peripheral joints of RA. Synovium and synovial fluid were sampled from 21 RA patients underwent arthroscopic synovectomy for inflamed peripheral joints. The variants of rheumatoid synovium were classified into the follicular and diffuse synovitis by hematoxylin and eosin staining, and the infiltrations of plasma cells in rheumatoid synovium were quantified under the light microscope. The synovial fluid levels of APRIL were measured with the enzyme-linked immunosorbent assay. The mean number of infiltrating plasma cells in synovium and the mean synovial fluid level of APRIL were significantly increased in follicular synovitis compared with those in diffuse synovitis (P = 0.009, and P = 0.018, respectively), and there was a highly positive association between the infiltrations of plasma cells and the synovial fluid levels of APRIL among all of the RA patients (Rs = 0.776, P < 0.001). These findings suggest that the local production of APRIL may be associated with the ectopic lymphoid neogenesis in rheumatoid synovium and may have a role in contributing to the infiltration of plasma cells in synovium within inflamed peripheral joints of RA.

Expression of CD147 on monocytes/macrophages in rheumatoid arthritis: its potential role in monocyte accumulation and matrix metalloproteinase production.

Monocytes/macrophages play an important role in rheumatoid arthritis (RA) pathogenesis. They can activate fibroblasts through many molecules, including IL-1 and tumor necrosis factor-alpha, but there have been very few reports on the role of CD147 in RA. In our study, the results of flow cytometry reveal that the mean fluorescence intensity (MFI) of CD147 expression on CD14+ monocytes of peripheral blood from RA patients was higher than that in normal control and ankylosing spondylitis (AS) patients. The MFI of CD147 expression on the CD14+ monocytes in RA synovial fluid was higher than that in RA peripheral blood. Immunohistochemical staining shows that CD147 expression in RA synovium correlated with matrix metalloproteinase (MMP)-1 expression. A double immunofluorescent assay shows that CD147 was expressed on CD68+ cells in RA synovium. The potential role of CD147 in cyclophilin A (CyPA)-mediated cell migration was studied using a chemotaxis assay in vitro and it was found that the addition of anti-CD147 antibody or a CD147 antagonistic peptide significantly decreased the chemotactic index of the mononuclear cells. The role of CD147 in MMP production and cell invasion in vitro were studied through the co-culture of human CD14+ monocytes or monocytic line THP-1 cells and human fibroblasts, as well as by gel zymography and an invasion assay. Significantly elevated release and activation of MMP-9 and/or MMP-2 were seen in the co-culture of human monocytes/THP-1 cells and fibroblasts compared with cultures of the cells alone. An increased number of cells invading through the filters in the invasion assays was also observed in the co-cultured cells. The addition of CD147 antagonistic peptide had some inhibitory effect, not only on MMP production but also on cell invasion in the co-culture. Our study demonstrates that the increased expression of CD147 on monocytes/macrophages in RA may be responsible for elevated MMP secretion, cell invasion and CyPA-mediated cell migration into the joints, all of which may contribute to the cartilage and bone destruction of RA. These findings, together with a better understanding of CD147, CyPA and RA, will help in the development of innovative therapeutic interventions for RA.

Gene expression of proprotein convertases in individual rat anterior pituitary cells and their regulation in corticotrophs mediated by glucocorticoids.

The subtilisin-like proprotein convertases (SPCs) are a family of serine proteinases that process secreted proteins at single or paired basic residues. Each SPC has been localized in the rat anterior pituitary, implying their importance in precursor processing in this tissue. The cellular distribution of each SPC has not been established in each hormone-producing cell type. We used double labeling in situ hybridization histochemistry to examine the mRNA distribution of five SPCs in relation to corticotrophs, thyrotrophs, lactotrophs, gonadotrophs, and somatotrophs. Our data demonstrated that SPC expression patterns were distinct, with each SPC expressed in more than one cell type. We noted that overlapping SPC expressions were the rule rather than the exception, suggesting potential SPC redundant functions. We examined the effects of adrenalectomy on corticotroph SPC expression. Most corticotrophs expressed SPC1, SPC3, and SPC4, but few corticotrophs expressed SPC2 or SPC6. After adrenalectomy, we observed increased mRNA levels for SPC1, SPC3, SPC4, and SPC6, but not for SPC2, in POMC-positive anterior pituitary cells. These increased levels were reversed by dexamethasone treatment. These data demonstrate the plasticity of SPCs expression in corticotrophs. SPCs may be directly involved in the mammalian stress response and may be important in hypothalamic-pituitary-adrenal axis homeostasis.