Regulation of mesenchymal stem cell differentiation by autophagy.

Autophagy, a process that isolates intracellular components and fuses them with lysosomes for degradation, plays an important cytoprotective role by eliminating harmful intracellular substances and maintaining cellular homeostasis. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity for self-renewal that can give rise to a subset of tissues and therefore have potential in regenerative medicine. However, a variety of variables influence the biological activity of MSCs following their proliferation and transplantation in vitro. The regulation of autophagy in MSCs represents a possible mechanism that influences MSC differentiation properties under the right microenvironment, affecting their regenerative and therapeutic potential. However, a deeper understanding of exactly how autophagy is mobilized to function as well as clarifying the mechanisms by which autophagy promotes MSCs differentiation is still needed. Here, we review the current literature on the complex link between MSCs differentiation and autophagy induced by various extracellular or intracellular stimuli and the molecular targets that influence MSCs lineage determination, which may highlight the potential regulation of autophagy on MSCs' therapeutic capacity, and provide a broader perspective on the clinical application of MSCs in the treatment of a wide range of diseases.

Potential mechanism of ginseng in the treatment of periodontitis based on network pharmacology and molecular docking.

OBJECTIVES: To explore the mechanism of ginseng in the treatment of periodontitis based on network pharmacology and molecular docking technology. METHODS: Potential targets of ginseng and periodontitis were obtained through various databases. The intersection targets of ginseng and periodontitis were obtained by using VENNY, the protein-protein interaction network relationship diagram was formed on the STRING platform, the core target diagram was formed by Cytoscape software, and the ginseng-active ingredient-target network diagram was constructed. The selected targets were screened for gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. The core targets of ginseng's active ingredients in treating periodontitis were analyzed by molecular docking technique. RESULTS: The 22 ginseng's active ingredients, 591 potential targets of ginseng's active ingredients, 2 249 periodontitis gene targets, and 145 ginseng-periodontitis intersection targets were analyzed. Ginseng had strong binding activity on core targets such as vascular endothelial growth factor A and epidermal growth factor receptor, as well as hypoxia induced-factor 1 (HIF-1) signaling pathway and phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway. CONCLUSIONS: Ginseng and its active components can regulate several signaling pathways such as HIF-1 and PI3K-Akt, thereby indicating that ginseng may play a role in treating periodontitis through multiple pathways.

Suppression of Cancer Cell Stemness and Drug Resistance via MYC Destabilization by Deubiquitinase USP45 Inhibition with a Natural Small Molecule.

Cancer stem cells (CSCs) play significant roles in cancer development, drug resistance and cancer recurrence. In cancer treatments based on the CSC characteristics and inducing factors, MYC is a promising target for therapeutic molecules. Although it has been regarded as an undrugable target, its stability tightly regulated by the ubiquitin-proteasome system offers a new direction for molecule targeting and cancer treatment. Herein we report our discoveries in this research area, and we have found that deubiquitinase USP45 can directly bind with MYC, resulting in its deubiquitination and stabilization. Further, USP45 overexpressing can upregulate MYC, and this overexpressing can significantly enhance cancer development, cancer cell stemness and drug resistance. Interestingly, without enhancing cancer development, MYC silencing with shRNA can only suppress USP45-induced stemness and drug resistance. Moreover, we have identified that USP45 can be specifically bound and inhibited by a natural small molecule (α-mangostin), in turn significantly suppressing USP45-induced stemness and drug resistance. Since USP45 is significantly expressed in cervical tumors, we have discovered that the combination of α-mangostin and doxorubicin can significantly inhibit USP45-induced cervical tumorigenesis in an animal model. In general, on the basis of our USP45 discoveries on its MYC deubiquitination and α-mangostin inhibition, suppressing USP45 has opened a new window for suppressing cancer development, stemness and drug resistance.

Roles of transducin-like enhancer of split (TLE) family proteins in tumorigenesis and immune regulation.

Mammalian transducin-like enhancer of split family proteins (TLEs) are homologous to Drosophila Groucho (Gro) and are essential transcriptional repressors. Seven TLE family members, TLE1-7, have been identified to date. These proteins do not bind DNA directly; instead, they bind a set of transcription factors and thereby inhibit target gene expression. Loss of TLEs in mice usually leads to defective early development; however, TLE functions in developmentally mature cells are unclear. Recent studies have revealed that TLEs are dysregulated in certain human cancer types and may function as oncogenes or tumor suppressors in different contexts. TLE levels also affect the efficacy of cancer treatments and the development of drug resistance. In addition, TLEs play critical roles in the development and function of immune cells, including macrophages and lymphocytes. In this review, we provide updates on the expression, function, and mechanism of TLEs; discuss the roles played by TLEs in tumorigenesis and the inflammatory response; and elaborate on several TLE-associated signaling pathways, including the Notch, Wnt, and MAPK pathways. Finally, we discuss potential strategies for targeting TLEs in cancer therapy.

Female fecundability is associated with pre-pregnancy allostatic load: Analysis of a Chinese cohort.

INTRODUCTION: Allostatic load (AL) is a practical index that reflects multi-system physiological changes which occur in response to chronic psychosocial stress. This study investigated the association between female pre-pregnancy allostatic load and time to pregnancy. MATERIAL AND METHODS: We enrolled 444 women who met the inclusion criteria and were attempting to achieve pregnancy. Their allostatic load scores at baseline were evaluated by nine indicators (systolic blood pressure, diastolic blood pressure, fasting plasma glucose, plasma cortisol, noradrenaline, interleukin-6, hypersensitive C-reactive protein, high density lipoprotein cholesterol and body mass index). The participants were followed up and their pregnancy outcome ascertained 1 year later; we then calculated time-to-pregnancy. Cox models were used to estimate fecundability ratios and their 95% confidence intervals (95% CI) for different allostatic load scores. RESULTS: The median allostatic load score was 1 with a range of 0-6. The females were divided into four groups according to allostatic load score: group A (allostatic load = 0, 150/444, 33.8%), group B (allostatic load = 1-2, 156/444, 35.1%), group C (allostatic load = 3-4, 100/444, 22.5%) and group D (allostatic load = 5-6, 38/444, 8.6%). The cumulative pregnancy rate over 12 months for the four groups (A-D) was 55.4%, 44.5%, 50.9% and 26.9%, respectively (log-rank test, p = 0.042). After adjusting for potential confounding factors, group D showed a 59% reduction of fecundability compared with group A (fecundability ratio = 0.41, 95% CI 0.21-0.83). CONCLUSIONS: Women with a higher allostatic load score may have lower fecundability. Our findings suggest that the assessment of allostatic load during pre-conception consultation would be highly prudent.

[Research Progress of Mesenchymal Stem Cells and Their Exosomes on Tumors].

In China, malignant tumor is the main cause of death in both urban and rural areas. Mesenchymal stem cells (MSCs) have multidirectional differentiation potential, self-renewal ability and good immunomodulatory properties. Exosomes, as important paracrine substances of MSCs, mediate information exchange and transmission between cells in tumor microenvironment and influence the occurrence and development of tumors. Recently, conflicting findings have been reported on the effects of MSCs and their exosomes on tumors. On the one hand, MSCs and their exosomes are tumorigenic and can target specific sites to inhibit tumor growth; On the other hand, there is also evidence that MSCs could affect tumor growth and migration as part of the tumor microenvironment. In this paper, we will review the relationship between MSCs and exosomes and tumorgenesis and development, as well as how MSCs and exosomes play different roles in tumorgenesis and development, in order to provide beneficial help for tumor diagnosis, prognosis and precise treatment.
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Periodontal ligament stem cells promote polarization of M2 macrophages.

Macrophages are widely distributed in a variety of tissues, and the different state of macrophages polarization is closely related to the occurrence, development, and prognosis of inflammation, including periodontitis, a chronic inflammatory disease leading to tooth loss worldwide. Periodontal ligament stem cells (PDLSCs) play a key role in immune regulation and periodontal tissues regeneration, contributing to cell-based therapy of periodontitis. However, the interactions between PDLSCs and macrophages are still elusive. The purpose of present study is to investigate the effect of PDLSCs conditioned medium (PDLSCs-CM) on the macrophage polarization and the possible mechanism. PDLSCs were isolated using tissue explant methods and characterized via multipotent differentiation test and examination of expression profiles of mesenchymal stem cells (MSCs) markers. The supernatant of PDLSCs was collected, centrifuged, filtered, and used as PDLSCs-CM. Then, PDLSCs-CM was cocultured with M0 macrophages or IL-4- and IL-13-induced M2 macrophages. The level of surface markers of M1/M2 macrophages and production of several proinflammatory or anti-inflammatory factors were evaluated by flow cytometric analysis and enzyme-linked immunosorbent assay, respectively. The associated genes and proteins involved in the JNK pathway were investigated to explore the potential mechanism that may regulate PDLSCs-CM-mediated macrophage polarization. PDLSCs expressed MSCs markers, including STRO-1, CD146, CD90, and CD73, and were negative for CD34 and CD45, could undergo osteogenic and adipogenic differentiation when cultured in defined medium. After incubation with PDLSCs-CM, no significant increase of CD80+ and HLA-DR+ M1 macrophages was shown while evaluated CD209+ and CD206+ M2 macrophages were observed. In addition, the levels of anti-inflammatory factors such as IL-10, TGF-ß, and CCL18 were increased instead of proinflammatory factors such as IL-1ß, TNF-α with PDLSC-CM treatment. There was a decrease of JNK expression on M0 macrophages by qRT-PCR analysis and an increase of protein phosphorylation on M0 macrophages after incubation with PDLSCs-CM. Furthermore, as for the enhancement of IL-4- and IL-13-mediated M2 polarization by PDLSCs-CM, the mRNA level of JNK decreased, and the protein phosphorylation level of JNK increased. In addition, the treatment of JNK pathway inhibitor, SP600125, could inhibit the expression and secretion level of anti-inflammatory factor such as IL-10 in M2 polarization induced by PDLSCs-CM. Collectively, PDLSCs were able to induce M2 macrophage polarization instead of M1 polarization, and capable of enhancing M2 macrophage polarization induced by IL-4 and IL-13. The JNK pathway was involved in the promotion of M2 macrophage polarization.

An evaluation of allogeneic freeze-dried concentrated growth factors biocompatibilityin vitroandin vivo.

This study evaluated the biocompatibility of allogeneic freeze-dried concentrated growth factors (AFD-CGFs)in vitroandin vivo.For thein vitroexperiments, bone marrow stem cells (BMSCs) were cultured in 10% fresh allogeneic concentrated growth factors (CGFs). AFD-CGF solution was used as the experimental group, and Dulbecco's modified Eagle medium was used as control. Transmission electron microscopy (TEM) showed that the cell ultrastructure was unchanged, and membranes were intact. Scanning electron microscopy, cell counting kit-8, and quantitative polymerase chain reaction indicated that BMSCs and differentiation were unchanged between AFD-CGFs versus control groups (allp> 0.05). Alkaline phosphatase activity was higher in CGF groups (peaked at 14 d) than in the control group. Regarding thein vivoexperiments, four beagles were used for surgery and the rest as controls. Beagles were sacrificed at 2 weeks to observe acute response and membrane absorption; at 12 weeks for wound healing and chronic damage to the liver. According to general observations and histology, the CGFs of all groups were absorbed 2 weeks afterin vivoimplantation. No sign of intolerance was observed. Histology showed a slight increase in immune cells appearing in the implantation area after 2 weeks. However, no or very few inflammatory and immune cells were detected 3 months after the operation. Based on the hematoxylin and eosin staining and TEM results, the ultrastructure of the liver tissue was unchanged. In general, the results suggest that AFD-CGFs are biocompatible and may be a promising option for tissue healing.

Novel myeloperoxidase-derived HLA-A2-restricted peptides as therapeutic targets against myeloid leukemia.

BACKGROUND AIMS: Human myeloperoxidase has been shown to be overexpressed in many types of leukemia, such as chronic myeloid leukemia, acute myeloid leukemia and myelodysplastic syndrome. The authors identified two myeloperoxidase-derived HLA-A2-restricted peptides, MY4 and MY8, as novel leukemia-associated antigens. METHODS: Ex vivo-elicited MY4- and MY8-specific cytotoxic T lymphocytes were generated, and tested for leukemia cell lysis in vitro and in NOD/SCID AML xenograft model. RESULTS: These MY4- and MY8-specific cytotoxic T lymphocytes killed leukemic blasts while sparing healthy donor bone marrow cells. In addition, co-injection of MY4- and MY8-specific cytotoxic T lymphocytes into nonobese diabetic/severe combined immunodeficiency mice with acute myeloid leukemia drastically reduced tumor burden in vivo. The authors also found that MY4- and MY8-specific T cells could be detected in the peripheral blood mononuclear cells of allogeneic stem cell transplant recipients. CONCLUSIONS: These antigen-specific T cells were significantly increased in blood samples from patients compared with healthy donors, suggesting that both MY4 and MY8 are immunogenic and that MY4- and MY8-specific cytotoxic T lymphocytes may play a role in reducing leukemia in vivo. Thus, the discovery of MY4 and MY8 as novel leukemia-associated antigens paves the way for targeting these antigens in immunotherapy against myeloid leukemia.

Dexamethasone promotes the endoplasmic reticulum stress response of bone marrow mesenchymal stem cells by activating the PERK-Nrf2 signaling pathway.

The pathogenesis of steroid-induced avascular necrosis of femoral head (SANFH) is complex, and there is a lack of effective early prevention method. The aim of the present study was to evaluate the effect of dexamethasone (DEX) on the biological behavior of bone marrow mesenchymal stem cells (BMSCs) and to explore the possibility of DEX in the clinical treatment of SANFH. The effect of DEX on the proliferation of BMSCs was evaluated by Counting Kit-8 assay, western blot assay, and enzyme-linked immunosorbent assay. Flow cytometry and western blot assay were performed to detect the effect of DEX on the apoptosis of BMSCs. Quantitative real-time PCR and western blot assay were performed to detect the effect of DEX on the expression of endoplasmic reticulum stress (ERS)-related genes. Immunoblotting analysis was conducted for detecting the nuclear-cytoplasmic distribution of Nrf2. DEX could significantly inhibit the proliferation of BMSCs and promote apoptosis of BMSCs. DEX could increase the expression of PERK, ATF6, and IRE1a, and induce nuclear translocation of Nrf2. The addition of ML385 could reverse the effect of DEX on BMSCs. DEX could activate the PERK-Nrf2 pathway to promote ERS and finally affect the cell proliferation and apoptosis of BMSCs.

Upregulation of TIGIT and PD-1 in Colorectal Cancer with Mismatch-repair Deficiency.

Background: The role of T cell Ig and ITIM domain (TIGIT) and programmed cell death-1 (PD-1) in colorectal cancer (CRC) with mismatch repair deficiency is unknown.Methods: This was a study of 60 CRC patients with mismatch repair deficiency and 30 healthy controls between June 2015 and October 2015.Results: The expression of Foxp3, PD-1, and TIGIT was higher in cancer tissues compared with adjacent mucosa (all P < .05). Patients with advanced TNM stage had a significantly higher expression of TIGIT (P = .025) and PD-1 (P = .020) than patients with early-stage CRC. The disease-free survival (DFS) of patients with high TIGIT (HR = 3.96, 95%CI: 1.34-11.69, P = .013) or PD-1 (HR = 214.8, 95%CI: 49.88-925.2, P < .001) expression were better. The overall survival (OS) of the patients with CRC and high expression of PD-1 was worse than those with low expression (HR = 4.01, 95%CI:1.26-12.69, P = .019).Conclusion: TIGIT and PD-1 are upregulated in CRC with mismatch repair deficiency and associated with TNM stage and DFS.

Engineering Macrophages via Nanotechnology and Genetic Manipulation for Cancer Therapy.

Macrophages play critical roles in tumor progression. In the tumor microenvironment, macrophages display highly diverse phenotypes and may perform antitumorigenic or protumorigenic functions in a context-dependent manner. Recent studies have shown that macrophages can be engineered to transport drug nanoparticles (NPs) to tumor sites in a targeted manner, thereby exerting significant anticancer effects. In addition, macrophages engineered to express chimeric antigen receptors (CARs) were shown to actively migrate to tumor sites and eliminate tumor cells through phagocytosis. Importantly, after reaching tumor sites, these engineered macrophages can significantly change the otherwise immune-suppressive tumor microenvironment and thereby enhance T cell-mediated anticancer immune responses. In this review, we first introduce the multifaceted activities of macrophages and the principles of nanotechnology in cancer therapy and then elaborate on macrophage engineering via nanotechnology or genetic approaches and discuss the effects, mechanisms, and limitations of such engineered macrophages, with a focus on using live macrophages as carriers to actively deliver NP drugs to tumor sites. Several new directions in macrophage engineering are reviewed, such as transporting NP drugs through macrophage cell membranes or extracellular vesicles, reprogramming tumor-associated macrophages (TAMs) by nanotechnology, and engineering macrophages with CARs. Finally, we discuss the possibility of combining engineered macrophages and other treatments to improve outcomes in cancer therapy.

LINC00861 inhibits the progression of cervical cancer cells by functioning as a ceRNA for miR­513b­5p and regulating the PTEN/AKT/mTOR signaling pathway.

Long non­coding RNAs (lncRNAs) have been discovered to serve important roles in a variety of types of cancer, including cervical cancer. The low expression of lncRNA long intergenic non­protein coding RNA 861 (LINC00861) is related to poor prognosis in ovarian cancer. However, the effects and underlying mechanisms of LINC00861 in cervical cancer remain largely unknown. The present study aimed to examine the role of LINC00861 in the development and progression of ovarian cancer and its underlying mechanisms. The expression levels of LINC00861 and microRNA (miR)­513b­5p were analyzed using reverse transcription­quantitative PCR analysis. Cell proliferation, migration and invasion were measured by using Cell Counting Kit­8, colony formation, wound healing and Transwell assays, respectively. A luciferase assay was used to determine whether miR­513b­5p targeted LINC00861 and PTEN. The expression of protein was measured by using western blot assay. The results of the present study discovered that LINC00861 expression levels were significantly downregulated in cervical cancer tissues and CaSki and ME­180 cell lines. Downregulated LINC00861 expression levels were identified to be associated with an advanced­stage, lymph node metastasis and the poor survival of patients with cervical cancer. Gene Set Enrichment Analysis revealed that the PI3K/AKT/mTOR signaling pathway was significantly enriched in cervical tumors expressing low expression levels of LINC00861 compared with tumors expressing high levels of LINC00861. The overexpression of LINC00861 reduced cervical cancer cell proliferation, migration, invasion and epithelial­mesenchymal transition (EMT) processes, upregulated PTEN protein expression levels and downregulated phosphorylated (p)­AKT and p­mTOR protein expression levels. The regulatory relationship between LINC00861, microRNA (miR)­513b­5p and PTEN was validated using a dual luciferase reporter gene assay. PTEN expression levels were significantly downregulated in the miR­513b­5p mimic group and significantly upregulated in the miR­513b­5p inhibitor group compared with the mimic NC and inhibitor NC in both cell lines. Furthermore, LINC00861 was suggested to serve as a competing endogenous RNA by sponging miR­513b­5p and consequently upregulating the expression levels of PTEN in cervical cancer cells. The expression of PTEN, the phosphorylation of Akt and mTOR and and the EMT phenotype were rescued following co­transfection with LINC00861 and miR­513b­5p mimics. In conclusion, the findings of the present study indicated that the LINC00861/miR­513b­5p axis may inhibit the progression of cervical cancer cells through the PTEN/AKT/mTOR signaling pathway to suppress the EMT process.

MiR-137-3p Inhibits Colorectal Cancer Cell Migration by Regulating a KDM1A-Dependent Epithelial-Mesenchymal Transition.

BACKGROUND: In colorectal cancer (CRC), miR-137-3p downregulation is associated with disease progression, but the mechanism is not fully understood. KDM1A, also known as LSD1, is upregulated in various cancer and promotes tumor metastasis. Interestingly, miR-137-3p is downregulated by hypoxia, which plays critical roles in tumor metastasis, and KDM1A is a miR-137-3p target gene in brain tumors. AIMS: To study if CRC metastasis is regulated by a hypoxia/miR-137-3p/KDM1A axis and if the epithelial-mesenchymal transition (EMT) process is involved. METHODS: We measured the levels of miR-137-3p, KDM1A, and some EMT markers in CRC biopsy tissues and cell lines. We also investigated the regulation of KDM1A by miR-137-3p and the effects of KDM1A inhibition on the EMT process and cell migration. RESULTS: We verified the low miR-137-3p and high KDM1A levels in CRC tumors. Inhibiting miR-137-3p upregulated KDM1A expression and promoted the invasiveness of CRC cells. KDM1A knockdown, or treatment with tranylcypromine, a specific KDM1A inhibitor, reduced the migration and invasion of CRC cells by inhibiting the EMT process. CRC cells cultured under hypoxic conditions expressed less miR-137-3p but more KDM1A than cells cultured under normal conditions, implying the involvement of miR-137-3p and KDM1A in hypoxia-induced tumor metastasis. CONCLUSIONS: We conclude that MiR-137-3p inhibits CRC cell migration by regulating a KDM1A-dependent EMT process. Our study suggests that restoring the expression of miR-137-3p or targeting KDM1A might be potential therapeutic strategies for CRC.

Association between polycystic ovary syndrome and the vaginal microbiome: A case-control study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Some evidence suggests that dysbiosis of the gut microbiota could be associated with PCOS clinical parameters, but little is known for the association between vaginal microbiome and PCOS. OBJECTIVE: To determine differences in the vaginal microbiome between women with PCOS and healthy control women. RESEARCH DESIGN AND METHODS: In this case-control study, the women with newly diagnosed PCOS (n = 39) and healthy controls (n = 40) were included from the hospital and maternal and child health centre, respectively. The vaginal swabs were collected, and microbiome structures were identified by 16S rRNA gene sequencing. The screening values for potential bacteria biomarker for PCOS were assessed by receiver operating characteristic (ROC) curve method. RESULTS: There was significant difference in vaginal bacterial structures between PCOS and healthy control women. The vaginal bacterial species in the PCOS group were more diverse than the control group (Simpson index for PCOS group vs. control group: median 0.49 vs. 0.80, P = .008; Shannon index: median 1.07 vs. 0.44, P = .003; Chao1 index: median 85.12 vs. 66.13, P < .001). The relative abundance of Lactobacillus crispatus in the PCOS group was significantly lower than controls (P = .001), and the relative abundance of Mycoplasma and Prevotella was higher than controls (P < .001, P = .002, respectively). The Mycoplasma genus could be a potential biomarker for PCOS screening, as ROC analysis showed that the area under the curve (AUC) for the relative abundance of Mycoplasma was 0.958 (95% CI: 0.901-0.999). Subgroup analyses also showed these associations would not change among the women with the same BMI level and vagina cleanliness grading. CONCLUSIONS: In the vaginal microbiome, the Mycoplasma genus was associated with PCOS. Further research is required to explore causal correlations between PCOS and the vaginal microbiome.

Orexin A associates with inflammation by interacting with OX1R/OX2R receptor and activating prepro-Orexin in cancer tissues of gastric cancer patients.

OBJECTIVE: Gastric cancer (GC) has been become the second leading cause for cancer-associated death. This study aimed to investigate Orexin A levels and associated receptors in tumor tissues of GC patients. PATIENTS AND METHODS: Forty-six consecutive gastric cancer patients (GC, n=46) and 13 chronic atrophic gastritis patients (CAG, n=13) were recruited. Meanwhile, 18 health individuals visiting Medical Examination Department were involved as control (N group, n=18). ELISA was used to examine Orexin A concentration. Immunohistochemistry assay was used to examine OX1R and OX2R. HE staining was applied to evaluate inflammation. qRT-PCR was employed to detect OX1R, OX2R, prepro-Orexin mRNAs. Serum Helicobacter pylori (H. pylori) infection was measured. RESULTS: Orexin A expression in GC patients was significantly up-regulated compared to N group and CAG group (p<0.05). Orexin A expression was increased in CAG group compared to N group (p<0.05). Gastric cancer tissues exhibited significantly obvious inflammation compared to N group and CAG group (p<0.05). OX1R and OX2R expressions were significantly down-regulated in GC group compared to N group and CAG group (p<0.05). OX1R and OX2R were lower significantly in GC group compared to CAG group (p<0.05). Prepro-Orexin was significantly depleted in tumor tissues of GC group compared to N group and CAG group (p<0.05). Orexin A expression was un-associated with gender, age and differential grades (p>0.05). CAG and GC patients demonstrated higher H. pylori infection rates. CONCLUSION: Orexin A was associated with inflammation by interacting with OX1R/OX2R receptor and activating prepro-Orexin in tumor tissues of gastric cancer patients.

JNK/AP1 Pathway Regulates MYC Expression and BCR Signaling through Ig Enhancers in Burkitt Lymphoma Cells.

In Burkitt lymphoma (BL), a chromosomal translocation by which the MYC gene is fused to an immunoglobulin (Ig) gene locus is frequently found. The translocated MYC gene is overexpressed, which is the major driver of BL tumorigenesis. Studies have shown that Ig enhancers are essential for MYC overexpression, but the involved mechanisms are not fully understood. In addition, the survival of BL cells relies on B-cell receptor (BCR) signaling, which is determined by the levels of Ig molecules expressed on the cell surface. However, whether MYC has any impact on Ig expression and its functional relevance in BL has not been investigated. Herein, we show that MYC upregulates Ig kappa (Igκ) expression in BL cells through two Igκ enhancers, the intronic enhancer (Ei) and the 3' enhancer (E3'). Mechanistically, by activating the JNK pathway, MYC induces the phosphorylation of c-Fos/c-Jun and their recruitment to AP1 binding sites in the Igκ enhancers, leading to the activation of the enhancers and subsequent Igκ upregulation. The AP1-mediated activation of the Igκ enhancers is also required for the expression of the translocated MYC gene, indicating positive feedback for the MYC overexpression in BL cells. Importantly, interrupting the JNK pathway inhibits both Igκ and MYC gene expression and suppresses BL cell proliferation. Our study not only reveals a novel mechanism underlying MYC overexpression in BL but also suggests that targeting the JNK pathway may provide a unique strategy to suppress BL tumorigenesis.

YY1 binds to the E3' enhancer and inhibits the expression of the immunoglobulin κ gene via epigenetic modifications.

The rearrangement and expression of immunoglobulin genes are regulated by enhancers and their binding transcriptional factors that activate or suppress the activities of the enhancers. The immunoglobulin κ (Igκ) gene locus has three important enhancers: the intrinsic enhancer (Ei), 3' enhancer (E3'), and distal enhancer (Ed). Ei and E3' are both required for Igκ gene rearrangement during early stages of B-cell development, whereas optimal expression of the rearranged Igκ gene relies on both E3' and Ed. The transcription factor YY1 affects the expression of many genes involved in B-cell development, probably by mediating interactions between their enhancers and promoters. Herein, we found that YY1 binds to the E3' enhancer and suppresses Igκ expression in B lymphoma cells by epigenetically modifying the enhancer. Knocking down YY1 enhanced Igκ expression, which was associated with increased levels of E2A (encoded by the TCF3 gene) and its binding to the E3' enhancer. Moreover, in germinal centre B cells and plasma cells, YY1 expression was reversely associated with Igκ levels, implying that YY1 might facilitate antibody affinity maturation in germinal centre B cells through the transient attenuation of Igκ expression.