查看更多>>摘要：Background: Metastatic organotropism is considered the end stage of malignancy with the mechanism still have some mysteries that have not been disclosed. Although the role of miR-106a is well studied, its involvement in the formation of peritoneal metastasis transported by exosomes is less discussed.Methods: Gastric cancer (GC)-derived exosomes were identified by transmission electron microscopy and the integration with peritoneal mesothelial cells (PMC) was confirmed by PKH-26 staining. Cell phenotype was assessed by EdU and flow cytometry. MiR-106a and its targets were authenticated by luciferase reporter assay. The mesothelial-to-mesenchymal transition (MMT) and extracellular matrix (ECM) degeneration were deter-mined and morphological transformation was measured by transwell assay. Immunodeficient mouse was con-ducted to investigate the tumorigenesis and tumor growth. The final was tissue analysis.Results: MiR-106a enrichment in GC-exosomes can be delivered and integrated into PMC to establish a proper pre-metastatic niche (PMN). We found that PMC could internalize exosomal-miR-106a and lead to increased apoptotic rate and decreased proliferative vitality. The direct target Smad7 and TIMP2 were proved to be effectively reduced by translocation of exosomal miR-106a. We confirmed that exosomal miR-106a was able to induce MMT and accelerate ECM through targeting Smad7 and TIMP2 to activate TGF-beta pathway. Animal model investigated that the tumorigenesis and tumor growth could be influenced by exosomes, and exosomal-miR-106a could promote the formation of xenograft tumor. Tissue analysis verified the ectopic miR-106a expression in gastric cancer metastasis.Conclusion: Our data suggest that exosomal miR-106a facilitates gastric cancer peritoneal dissemination by integrating PMC to destroy mesothelial barrier.
查看更多>>摘要：Ubiquitin E3-ligases are recruited at different steps of TNF-alpha-induced NF-kappa B activation; however, their role in temporal regulation of the pathway remains elusive. The study systematically identified TRIMs as potential feedback regulators of the TNF-alpha-induced NF-kappa B pathway. We further observed that TRIM15 is "late" response TNF-alpha-induced gene and inhibits the TNF-alpha-induced NF-kappa B pathway in several human cell lines. TRIM15 promotes turnover of K63-linked ubiquitin chains in a PRY/SPRY domain-dependent manner. TRIM15 interacts with TAK1 and inhibits its K63-linked ubiquitination, thus NF-kappa B activity. Further, TRIM15 interacts with TRIM8 and inhibits cytosolic translocation to antagonize TRIM8 modualted NF-kappa B. TRIM8 and TRIM15 also show functionally inverse correlation in psoriasis condition. In conclusion, TRIM15 is TNF-alpha-induced late response gene and inhibits TNF-alpha induced NF-kappa B pathway hence a feedback modulator to keep the proinflammatory NF-kappa B pathway under control.
查看更多>>摘要：Elucidating the mechanism of the osteogenic phenotypic transdifferentiation of vascular smooth muscle cells (VSMCs) is the key to determining the diagnosis and treatment of arterial medial calcification (AMC). Long noncoding RNAs (lncRNAs) have been reported to participate in the regulation of vascular physiology and pathology. Here, we investigated the effect and mechanism of the lncRNA H19 on the osteoblastic differentiation of VSMCs induced by high phosphorus. H19 was expressed at high levels in high phosphorus-induced primary rat VSMCs. Further experiments indicated that H19 played a positive role in the osteoblast phenotypic transition by suppressing miR-103-3p expression and subsequently promoting osteoblast-specific marker expression, including bone morphogenetic protein 2 (BMP-2) and osteopontin (OPN). Mechanistically, we recognized RUNX family transcription factor 2 (Runx2) as a direct target of miR-103-3p. Moreover, H19 directly interacted with miR-1033p, and overexpression of miR-103-3p reversed the upregulation of Runx2 induced by H19. Therefore, H19 positively regulated Runx2 expression by sponging miR-103-3p and promoted the osteoblast phenotypic transition in VSMC calcification. Collectively, the lncRNA H19 promoted osteogenic differentiation by modulating the miR-103-3p/Runx2 axis in the process of VSMC calcification induced by a high phosphorus concentration. The current study provided new insights into an important role for the lncRNA H19 as a miRNA sponge in VSMCs and supplied novel insights into lncRNA-directed diagnostics and therapeutics for vascular calcification.
查看更多>>摘要：Tuberculosis caused by Mycobacterium tuberculosis (Mtb) remains a tremendous global public health concern. Deciphering the biology of the pathogen and its interaction with host can inspire new measures against tuberculosis. Phosphorylation plays versatile and important role in the pathogen and host physiology, such as virulence, signaling and immune response. Proteome-wide phosphorylation of Mtb and its infected host cells, namely phosphoproteome, can inform the post-translational modification of the interaction network between the pathogen and the host, key targets for novel antibiotics. We summarized the phosphoproteome of Mtb, as well as the host, focusing on potential application for new measures against tuberculosis.
查看更多>>摘要：Epithelial splicing regulatory protein 1 (ESRP1) is overexpressed in the majority of cancer types, while downregulated in a few cancers, thus it has emerged as a tumorigenic or a tumor suppressor depending on disease context and cell type. Moreover, the underlying molecular mechanism of ESRP1 is poorly understood in cancer progression. Here, we initially analyzed Clinical Proteomic Tumor Analysis Consortium (CPTAC), colon tissue microarray, and colon cancer cells to evaluate the ESRP1 expression levels in colorectal cancer subtypes. The association between the expression of ESRP1 and cell death signaling pathways was evaluated in colon cancer cells. Furthermore, silencing ESRP1 was performed to detect the relation between ESRP1 and apoptosis-inducing factor (AIF). Subsequently, translocation of AIF and apoptosis were analyzed by immunofluorescence assay and FACS, respectively. ESRP1 is found to be expressed at high levels in the early stage, and gradually decreases with the increasing colorectal cancer stage, wherein epithelial cell to mesenchymal cell transition (EMT) occurs during cancer progression. Moreover, ESRP1 silencing in HCT116 colorectal cancer cells reveals the translocation of the caspase-independent cell death marker AIF to the nucleus, thereby enhancing the DNA damage response, which inevitably induces cancer cell death. Our results demonstrate that silencing ESRP1 in colorectal cancer cells promotes HCT116 cell death by inducing caspase-independent cell death via regulation of CD44 alternative splicing. Collectively, our findings provide an insight into ESRP1 as a therapeutic target in colon cancer.
查看更多>>摘要：RelB confers the aggressiveness to prostate cancer (PC) cells. Exosomes modulate the oncogenesis and progression of PC. We aimed to identify the downstream molecule in the exosomes, by which RelB increases the aggressiveness of DU145. Totally, 137 upregulated and 55 downregulated exosomal proteins were identified from RelB-knockdown DU145 cells by Liquid Chromatography-Mass Spectrometry. UALCAN, GeneMANIA and tissue microarray analysis revealed that intercellular adhesion molecule-1 (ICAM1) was positively related to and co-expressed with RelB in PC. Luciferase reporter assay revealed that RelB bound directly to the promoter of ICAM1. ICAM1 overexpression enhanced the migration and invasion abilities of DU145 cells. Exposure to exosomes derived from ICAM1 overexpressing cells (hICAM1-exo) strengthened the aggressiveness of RelBknockdown cells, especially the migration and invasion capabilities. Mechanistically, the expression of ICAM1, Integrin beta 1, MMP9 and uPA were upregulated in RelB-knockdown cells upon hICAM1-exo treatment. Exosomal ICAM1 is the key molecule regulated by RelB, which increased the aggressiveness of DU145. The study suggests that cell-cell communication via exosomal ICAM1 is a novel mechanism by which RelB promotes PC progression.
查看更多>>摘要：The hyperglycemic microenvironment induced by diabetes mellitus aggravates the inflammatory response, in which the IRE1 alpha signal transduction pathway of the unfolded protein response (UPR) participates. However, the mechanism by which hyperglycemia regulates the IRE1 alpha signaling pathway and affects endoplasmic reticulum (ER) homeostasis in human gingival epithelium in periodontitis with diabetes mellitus remains unknown. Our current data provide evidence that diabetes mellitus causes a hyperinflammatory response in the gingival epithelium, which accelerates periodontal inflammation. Next, we assessed UPR-IRE1 alpha signaling in periodontitis with diabetes mellitus by examining human clinical gingival epithelium samples from healthy subjects, subjects with periodontitis and subjects with periodontitis with diabetes mellitus and by in vitro challenge of human epithelial cells with a hyperglycemic microenvironment. The results showed that a hyperglycemic microenvironment inhibited the IRE1 alpha/XBP1 axis, decreased the expression of a UPR target gene (GRP78), and ultimately impaired the UPR, causing ER stress to be prolonged or more severe in human gingival epithelium. Subsequently, RNA sequencing (RNA-seq) data was analyzed to investigate the expression of ER-related genes in human gingival epithelium. Experiments verified that the mechanism by which periodontitis is aggravated in individuals with diabetes mellitus may involve decreased SERPINH1 expression. Furthermore, experiments in SERPINH1knockdown and SERPINH1-overexpression models established in vitro indicated that SERPINH1 might act as an activator of IRE1 alpha, maintaining human gingival epithelium homeostasis and reducing proinflammatory cytokine expression by preventing prolonged ER stress induced by high-glucose conditions. In conclusion, regulation of the UPR transducer IRE1 alpha by SERPINH1 alleviates periodontitis with diabetes mellitus by mitigating prolonged ER stress. This finding provides evidence for the further study of periodontitis with diabetes mellitus.
查看更多>>摘要：DM (diabetic mellitus) and its common vascular complications VC (vascular calcification), are increasingly harmful to human health. In recent years, the research on the relationship between DM and VC is also deepening. Hypoxia, as one of the pathogenic factors of many disease models, is also closely related to the occurrence of DM and VC. There are some studies on the role of hypoxia in the pathogenesis of DM and VC respectively, but no one has made an in-depth summary of the systematic connection between hypoxia, DM and VC. Therefore, what we want to review in this article are the relationship between DM, VC and hypoxia, respectively, as well as the role of hypoxia in the development of DM and VC, which has little concern but is a novel and potentially target that may provide some new ideas for the prevention and treatment of DM, VC, especially diabetic VC.
查看更多>>摘要：Although FTO, as an eraser of N6-methyladenosine (m(6)A), plays context-dependent tumor-suppressive and oncogenic roles in various cancer type, underlying molecular events of its aberrant expression in cancers is complex and still poorly understood. Here we show that miR-155 directly targets FTO to negatively regulate its expression and increased m6A level in ccRCC. Combining bioinformatics analysis and luciferase reporter assays, we identified that miR-155 directly bound to the 3'UTR of FTO mRNA and reduced FTO protein levels in ccRCC cells. Moreover, cell function assays, xenografts assays and m(6)A dot blot assays revealed that overexpression of miR-155 enhanced tumor cell proliferation and global mRNA m6A level, while decreasing apoptosis in a FTOdependent manner. Collectively, our data demonstrates the functional importance of miR-155 in regulating FTO expression and global mRNA m6A level, and provides profound insights into ccRCC tumorigenesis.
查看更多>>摘要：Paclitaxel (PTX) is a common antineoplastic drug whose functionality is often restricted by drug resistance. Solute carrier organic anion transporter family member 1B3 (SLCO1B3) is a PTX influx transporter and its low expression has been proved to be relevant with PTX resistance. It has been widely reported that AMP-activated protein kinase (AMPK) could re-sensitize tumor cells to PTX. Our gene array result demonstrates AMPK up-regulated SLCO1B3. In this paper, we have tried to explain the relationships between PTX, SLCO1B3 and AMPK. First, we have verified the proliferative inhibition of PTX on A549 and found that PTX could inhibit A549 cells proliferation. Then, we have explored the relationship between SLCO1B3 and PTX: SLCO1B3 expression significantly decreased when A549 cells were treated with PTX or in A549 PTX resistant cells (A549-PTX) and the intracellular PTX concentration in A549-PTX was also lower. When treated with metformin/LKB1, both SLCO1B3 expression and intracellular PTX concentration have increased. Knockdown of AMPK has induced decreased SLCO1B3 expression. Moreover, in vitro and in vivo experiments have showed that metformin not only obviously inhibited A549-PTX tumor xenograft and A549-PTX proliferation alone, but also enhanced PTX efficacy to A549-PTX and this may be relevant to SLCO1B3. To verify it, we have treated A549 cells with AMPK both activators and an inhibitor, and then found that AMPK activators could weaken the PTX effect in inhibiting SLCO1B3 while its inhibitor has opposite effect. With knockdown of SLCO1B3, the effect of AMPK in re-sensitizing A549 to paclitaxel has decreased. To sum up, activation of AMPK can up-regulate SLCO1B3 expression, enhance the sensitivity of A549 cells to PTX, providing a new way to re-sensitize PTX resistance.
NSTL
Elsevier