Diagnostic value of BHI-V4 for heterogeneous and vancomycin-intermediate Staphylococcus aureus isolates: a systematic review and meta-analysis.

BACKGROUND: Brain-heart infusion agar supplemented with 4 µg/mL of vancomycin (BHI-V4) was commonly used for the detection of heterogeneous (hVISA) and vancomycin-intermediate Staphylococcus aureus (VISA). However, its diagnostic value remains unclear. This study aims to compare the diagnostic accuracy of BHI-V4 with population analysis profiling with area under the curve (PAP-AUC) in hVISA/VISA. METHODS: The protocol of this study was registered in INPLASY (INPLASY2023120069). The PubMed and Cochrane Library databases were searched from inception to October 2023. Review Manager 5.4 was used for data visualization in the quality assessment, and STATA17.0 (MP) was used for statistical analysis. RESULTS: In total, eight publications including 2153 strains were incorporated into the meta-analysis. Significant heterogeneity was evident although a threshold effect was not detected across the eight studies. The summary receiver operating characteristic (SROC) was 0.77 (95% confidence interval [CI], 0.74-0.81). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic score and diagnostic odds ratio were 0.59 (95% CI: 0.46-0.71), 0.96 (95%CI: 0.83-0.99), 14.0 (95% CI, 3.4-57.1), 0.43 (95%CI, 0.32-0.57), 3.48(95%CI, 2.12-4.85) and 32.62 (95%CI, 8.31-128.36), respectively. CONCLUSION: Our study showed that BHI-V4 had moderate diagnostic accuracy for diagnosing hVISA/VISA. However, more high-quality studies are needed to assess the clinical utility of BHI-V4.

Adaptive physiological and metabolic alterations in Staphylococcus aureus evolution under vancomycin exposure.

Staphylococcus aureus can develop antibiotic resistance and evade immune responses, causing infections in different body sites. However, the metabolic changes underlying this process are poorly understood. A variant strain, C1V, was derived from the parental strain C1 by exposing it to increasing concentrations of vancomycin in vitro. C1V exhibited a vancomycin-intermediate phenotype and physiological changes compared to C1. It showed higher survival rates than C1 when phagocytosed by Raw264.7 cells. Metabolomics analysis identified significant metabolic differences pre- and post-induction (C1 + SC1 vs. C1V + SC1V: 201 metabolites) as well as pre- and post-phagocytosis (C1 vs. SC1: 50 metabolites; C1V vs. SC1V: 95 metabolites). The variant strain had distinct morphological characteristics, decreased adhesion ability, impaired virulence, and enhanced resistance to phagocytosis compared to the parental strain. Differential metabolites may contribute to S. aureus ' resistance to antibiotics and phagocytosis, offering insights into potential strategies for altering vancomycin nonsusceptibility and enhancing phagocyte killing by manipulating bacterial metabolism.

Luteolin Inhibits Fibrillary ß-Amyloid1-40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways.

Amyloid-ß peptides (Aß) exist in several forms and are known as key modulators of Alzheimer's disease (AD). Fibrillary Aß (fAß) has been found to disrupt the blood-brain barrier (BBB) by triggering and promoting inflammation. In this study, luteolin, a naturally occurring flavonoid that has shown beneficial properties in the central nervous system, was evaluated as a potential agent to preserve barrier function and inhibit inflammatory responses at the BBB that was injured by fAß1-40. We established an in vitro BBB model by co-culturing human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) under fAß1-40-damaged conditions and investigated the effect of luteolin by analyzing cellular toxicity, barrier function, cytokine production and inflammation-related intracellular signaling pathways. Our results demonstrated that, in cells injured by fAß1-40, luteolin increased cell viability of hBMECs and hAs. The cytoprotection of the co-culture against the damage induced by fAß1-40 was also increased at both the apical and basolateral sides. Luteolin protected the barrier function by preserving transendothelial electrical resistance and relieving aggravated permeability in the human BBB model after being exposed to fAß1-40. Moreover, in both the apical and basolateral sides of the co-culture, luteolin reduced fAß1-40-induced inflammatory mediator and cytokine production, including cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1 ß (IL-1ß), interleukin 6 (IL-6), and interleukin 8 (IL-8), however it did not show sufficient effects on scavenging intracellular reactive oxygen species (ROS) in hBMECs and hAs. The mechanism of BBB protection against fAß1-40-induced injury may be related to the regulation of inflammatory signal transduction, which involves inhibition of p38 mitogen-activated protein kinase (MAPK) activation, downregulation of phosphorylated inhibitory κB kinase (phosphor-IKK) levels, relief of inhibitory κB α (IκBα) degradation, blockage of nuclear factor κB (NF-κB) p65 nuclear translocation, and reduction of the release of inflammatory cytokines. Moreover, the employment of p38 MAPK and NF-κB inhibitors reversed luteolin-mediated barrier function and cytokine release. Taken together, luteolin may serve as a potential therapeutic agent for BBB protection by inhibiting inflammation following fAß1-40-induced injury.

Roles of Rictor alterations in gastrointestinal tumors (Review).

Gastrointestinal tumors account for five of the top 10 causes of mortality from all cancers (colorectal, liver, stomach, esophageal and pancreatic cancer). Mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in various human cancers. As a core component of the mTOR complex 2 (mTORC2), Rictor is a key effector molecule of the PI3K/Akt pathway. A high alteration rate of Rictor has been observed in gastrointestinal tumors, and such Rictor alterations are often associated with resistance to chemotherapy and related adverse clinical outcomes. However, the exact roles of Rictor in gastrointestinal tumors remain elusive. The aim of the present study was to critically discuss the following: i) Mutation and biological characteristics of Rictor in tumors with a detailed overview of Rictor in cell proliferation, angiogenesis, apoptosis, autophagy and drug resistance; ii) the role of Rictor in tumors of the digestive system, particularly colorectal, hepatobiliary, gastric, esophageal and pancreatic cancer and cholangiocarcinoma; and iii) the current status and prospects of targeted therapy for Rictor by inhibiting Akt activation. Despite the growing realization of the importance of Rictor/mTORC2 in cancer, the underlying mechanistic details remain poorly understood; this needs to change in order for the development of efficient targeted therapies and re­sensitization of therapy­resistant cancers to be made possible.

Clinical and pathological characteristics of and predictive model for colorectal neuroendocrine tumors.

Background: The incidence of colorectal neuroendocrine tumors (NETs) is increasing, causing a social burden. At present, there is no specific prognostic model for colorectal NETs. Thus, an accurate model is needed to predict the prognosis of patients with colorectal NETs. Aim: We aimed to create a new nomogram to predict the prognosis of patients with colorectal NETs. Furthermore, we compared nomogram we established and the 8th edition of the AJCC TNM staging system in terms of prediction ability and accuracy. Methods: A total of 3353 patients with colorectal NETs were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analyses were used to assess overall survival (OS) and cancer-specific survival (CSS). Additionally, LASSO regression was used to select variables for constructing the nomogram. Furthermore, the C-index and time-dependent receiver operating characteristic (tdROC) curve were used to evaluate the nomogram. Decision curve analysis (DCA) was performed to compare the clinical utility of the nomogram with that of the TNM system. An external validation cohort (N = 61) was established to evaluate the nomogram's prediction accuracy. Results: A total of 9 factors (age, sex, marital status, tumor size, T stage, M stage, N stage, grade, and surgery) were selected based on the results of LASSO analysis. The C-indexes of the nomogram in the training and validation sets were 0.807 and 0.775, respectively, which indicated that the nomogram had better prediction accuracy than TNM staging (C-index = 0.700 in the training set and 0.652 in the validation set). The C-index of the nomogram in the external validation cohort was 0.954, indicating that the nomogram had satisfactory prediction accuracy. The results of DCA revealed that the survival nomogram possessed greater utility in clinical practice. Conclusion: We determined the OS and CSS of patients with colorectal NETs and developed a robust and clinically useful survival nomogram.

Endoscopic diagnosis and treatment of superficial non-ampullary duodenal epithelial tumors: A review.

The surface of the small bowel mucosa is covered more than any other section of the digestive canal; however, the overall prevalence of small bowel tumors of the whole gastrointestinal tract is evidently low. Owing to the improvement in endoscopic techniques, the prevalence of small bowel tumors has increased across multiple countries, which is mainly due to an increase in duodenal tumors. Superficial non-ampullary duodenal epithelial tumors (SNADETs) are defined as tumors originating from the non-ampullary region in the duodenum that share similarities and discrepancies with their gastric and colorectal counterparts in the pathogenesis and clinicopathologic characteristics. To date, white light endoscopy (WLE) remains the cornerstone of endoscopic diagnosis for SNADETs. Besides, narrow-band imaging (NBI) techniques and magnifying endoscopy (ME) have been widely used in the clinic and endorsed by multiple guidelines and consensuses for SNADETs' evaluation. Confocal laser endomicroscopy (CLE), endocytoscopy (ECS), and artificial intelligence (AI) are also up-and-coming methods, showing an exceptional value in the diagnosis of SNADETs. Similar to the endoscopic treatment for colorectal polyps, the choices for SNADETs mainly include cold snare polypectomy (CSP), endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and laparoscopic endoscopic cooperative surgery (LECS). However, owing to the narrow lumen, rich vascularity, weak muscle layer, abundant Brunner's gland, and the hardship of endoscope control, the duodenum ranks as one of the most dangerous operating areas in the digestive tract. Therefore, endoscopists must anticipate the difficulties in endoscopic maneuverability, remain aware of the increased risk of complications, and then select the appropriate treatment according to the advantages and disadvantages of each method.

Frailty and pre-frailty with long-term risk of elderly-onset inflammatory bowel disease: A large-scale prospective cohort study.

PURPOSE: To investigate the prospective association of frailty status with the long-term risk of elderly-onset IBD in a large prospective cohort. METHODS: Participants free of IBD and cancer at enrollment from the UK Biobank cohort were included. Baseline pre-frail and frail status was measured by Fried phenotype including weight loss, exhaustion, low grip strength, low physical activity and slow walking pace, defined as meeting one or two criteria and meeting three or more criteria. Primary outcome was elderly-onset IBD, including elderly-onset ulcerative colitis (UC) and Crohn's disease (CD). Multivariable Cox regression was conducted to examine the related associations. RESULTS: Overall, 417,253 participants (aged 56.18 ± 8.09 years) were included. Of whom, 19,243 (4.6 %) and 188,219 (45.1 %) were considered frail and pre-frail, respectively. During a median of 12.4 years follow-up, 1503 elderly-onset IBD cases (1001 UC, 413 CD, and 89 IBD-Unclassified) were identified. Compared with non-frail, individuals with frail (HR=1.40, 95 %CI: 1.13-1.73) and pre-frail (HR=1.15, 1.03-1.28) showed significantly higher risk of elderly-onset IBD after multivariable adjustment (Ptrend<0.001). The positive association was more evident regarding risk of elderly-onset CD (HR=2.16, 1.49-3.13 for frail; HR=1.49,1.20-1.85 for pre-frail; Ptrend<0.001). Sensitivity analyses and subgroup analyses according to age, gender and body mass index (BMI) demonstrated similar results. CONCLUSIONS: Frailty and pre-frailty are associated with increased risk of elderly-onset IBD, particularly elderly-onset CD.

Proteomic and Phenotypic Studies of Mycoplasma pneumoniae Revealed Macrolide-Resistant Mutation (A2063G) Associated Changes in Protein Composition and Pathogenicity of Type I Strains.

Mycoplasma pneumoniae (MP) is an important respiratory pathogen, the prevalence of macrolide-resistant MP (mainly containing A2063G mutation in 23S rRNA) increased in recent years. Epidemiological studies suggest a higher prevalence of type I resistant (IR) strains than corresponding sensitive (IS/IIS) strains, but not type II resistant (IIR) strains. Here, we aimed to analyze the factors underlying the altered prevalence of IR strains. First, proteomic analyses exhibit the protein compositions were type specific, while more differential proteins were detected between IS and IR (227) than IIS and IIR strains (81). mRNA level detection suggested posttranscriptional regulation of these differential proteins. Differential protein-related phenotypic changes were also detected: (i) P1 abundance was different between genotypes (I < II, IR < IS), the adhesion of MPs showed accordance to P1 abundance within IS and IIS strains; (ii) type I, especially IR, strains had a higher proliferation rate, which is potentially associated with differential proteins participating in glycolysis and one carbon pool metabolisms; (iii) A549 cells infected with IR strains had lower activity of caspase-3 and higher levels IL-8, but the differences were not significant between groups (P > 0.05). Correlations of P1 abundance to caspase-3 activity and proliferation rate to the level of IL-8 were obtained. These results suggest changes in protein composition influenced the pathogenicity of MP, especially in IR strains, which may impact the prevalence of MP strains of different genotypes. IMPORTANCE The prevalence of macrolide-resistant MPs increased the difficulty in treatment of MP infections and posed potential threats to children's health. Epidemiological studies showed a high prevalence of IR-resistant strains (mainly A2063G in 23S rRNA) in these years. However, the trigger mechanisms for this phenomenon are not clear. In this paper, proteomic and phenotypic studies suggest that IR strains have reduced levels of multiple adhesion proteins and increased proliferation rate, which may lead to higher transmission rate of IR strains in the population. This suggests that we should pay attention to the prevalence of IR strains.

Corrigendum: Tilianin extracted from Dracocephalum moldavica L. induces intrinsic apoptosis and drives inflammatory microenvironment response on pharyngeal squamous carcinoma cells via regulating TLR4 signaling pathways.

[This corrects the article DOI: 10.3389/fphar.2020.00205.].

miR-23b-3p rescues cognition in Alzheimer's disease by reducing tau phosphorylation and apoptosis via GSK-3ß signaling pathways.

Dysregulated microRNA (miRNA) expression in the brain can contribute to cognitive dysfunction and aberrant tau hyperphosphorylation in Alzheimer's disease (AD). Several studies have reported a role for microRNA-23b-3p (miR-23b-3p) in various neurologic disorders; however, its involvement in cognition-related functions remains unclear. In the present study, we investigated the potential therapeutic effects and mechanisms of miR-23b-3p in AD. miRNA profiles in the cortex of amyloid precursor protein (APP)/presenilin 1 (PS1) double transgenic mice (APP/PS1 mice) demonstrated that miR-23b-3p was reduced. This decrease was verified in APPswe cells, SAMP8 mouse brains, and plasma from AD patients. Furthermore, glycogen synthase kinase-3ß (GSK-3ß), a major tau kinase implicated in tau pathology, was identified as a target of miR-23b-3p. Functional in vivo studies demonstrated that intracerebroventricular delivery of miR-23b-3p in APP/PS1 mice ameliorated cognitive deficits, histopathological changes, and tau phosphorylation immunoreactivity at several sites by inhibiting GSK-3ß expression and activation. Similarly, the upregulation of miR-23b-3p in APPswe cells inhibited GSK-3ß-mediated tau hyperphosphorylation, Aß1-42 generation, and neuronal apoptosis, resulting in the suppression of the GSK-3ß/p-tau and Bax/caspase-3 pathways. Collectively, our findings strongly support the hypothesis that miR-23b-3p plays a neuroprotective role in AD, thereby identifying miR-23b-3p as a promising therapeutic target for AD.

Prognostic gene profiles in the tumor microenvironment of ovarian serous adenocarcinoma.

Ovarian serous adenocarcinoma is one of the most common and fatal malignancies among women worldwide. The tumor microenvironment plays a critical role in tumor initiation, proliferation, and metastasis. Immune scores and stromal scores of the tumor microenvironment were determined using the ESTIMATE. Immune cell infiltration was assessed using TIMER and differentially expressed genes (DEGs) were determined using the R/Bioconductor package of edgeR. Survival analysis was carried out using a univariate Cox model and Kaplan-Meier survival, and gene functional information was obtained through Gene Ontology and KEGG pathway analysis. Survival analysis revealed 39 DEGs that significantly influenced the prognosis of ovarian serous adenocarcinoma patients and were correlated with immune cell abundance. Functional enrichment and protein-protein interaction network analyses further indicated that these genes are primarily involved in immune-related responses. Finally, we verified the prognostic value of these genes via GEO. The present results reveal the genes associated with the tumor microenvironment of ovarian adenocarcinoma, potentially providing prognostic information.

Rictor Activates Cav 1 Through the Akt Signaling Pathway to Inhibit the Apoptosis of Gastric Cancer Cells.

BACKGROUND: Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) protein is a core subunit of mammalian target of rapamycin complex 2, and is associated with cancer progression. However, the biological function of Rictor in cancer, particularly its clinical relevance in gastric cancer (GC) remains largely unknown. METHODS: Rictor expression and its association with clinicopathologic characteristics in GC were analyzed by immunohistochemistry. Effect of Rictor and Caveolin-1 (Cav 1) on GC cells apoptosis was evaluated via overexpression experiment in vitro. Mechanisms of Rictor and Cav 1 in GC were explored through overexpression and knockdown, by immunofluorescence and western blot analyses. RESULTS: Rictor was upregulated in GC, and mainly located in the cytoplasm of cancer cells. Moreover, higher Rictor levels were associated with worse prognosis. Rictor could inhibit GC cell apoptosis and promote cell growth in vitro. The results of immunofluorescence revealed that Cav 1 localized in GC cell membrane but did not co-localize with Rictor. Further, Rictor regulated apoptosis-related proteins, long non-coding RNAs and also activated cellular signaling, thereby positively regulating Cav 1 expression. This effect was attenuated by the Akt inhibitor ly294002. Cav 1 did not significantly affect the ability of Rictor to inhibit tumor cell apoptosis. CONCLUSIONS: Rictor is upregulated in GC and associated with worse prognosis. It inhibits tumor apoptosis and activates Cav 1 through the Akt signaling pathway to inhibit the apoptosis of GC cells. Rictor is, therefore, a promising prognostic biomarker and possible therapeutic target in GC patients.

Immune-related gene signature predicts overall survival of gastric cancer patients with varying microsatellite instability status.

PURPOSE: Gastric cancer (GC) is one of the most common and fatal malignancies globally. While microsatellite instability (MSI) index has earlier been correlated with survival outcome in gastric cancer patients, the present study aims to construct a risk-stratification model based on immune-related genes in GC patients with varying MSI status. RESULTS: The univariate and multivariate Cox regression analyses identified SEMA7A, NUDT6, SCGB3A1, NPR3, PTH1R, and SHC4 as signature genes, which were used to build the prognostic model for GC patients with microsatellite instability-low (MSI-L) and microsatellite stable (MSS). Whereas, for GC patients with microsatellite instability-high (MSI-H), prognostic model was established with three genes (SEMA6A, LTBP1, and BACH2), based on the univariate and multivariate Cox regression, and Kaplan-Meier survival analyses. CONCLUSION: The prognostic immune-related gene signature identified in this study may offer new targets for personalized treatment and immunotherapy for GC patients with MSI-H or MSI-L/MSS status. METHODS: The Cancer Genome Atlas (TCGA) and ImmPort databases were used to extract expression data and to explore prognostic genes from the immune-related genes (IRGs), respectively. Univariate and multivariate Cox regression analysis were applied to identify IRGs correlated with patient prognosis. The regulatory network between prognostic IRGs and TFs were performed using R software.

Tilianin Extracted From Dracocephalum moldavica L. Induces Intrinsic Apoptosis and Drives Inflammatory Microenvironment Response on Pharyngeal Squamous Carcinoma Cells via Regulating TLR4 Signaling Pathways.

Human pharyngeal squamous cell carcinoma is highly invasive and proliferative, and exhibits an extremely low 5-year survival rate due to poor understanding of the underlying pathogenic mechanisms, and lack of efficient treatment. It has been shown that the immunosuppressive microenvironment created by tumor cells impairs the immune response against tumor progression, thereby affecting the prognosis for tumor patients. Thus, to improve therapeutic efficacy, it is critical to identify novel drugs with immunoinflammatory modulatory properties to treat tumor immune evasion. Tilianin, the main ingredient of total flavonoids extracted from Dracocephalum moldavica L., has multiple biological functions, including cardiovascular protective effects, anti-tumor effects, and anti-inflammatory effects. In the present study, the suppressive effects of tilianin on human pharyngeal squamous cell carcinoma were investigated and the underlying mechanisms in regulating the tumor immunosuppressive microenvironment were explored. The cytotoxicity of tilianin on FaDu cells was determined by CCK-8 and clone formation assays. Moreover, the levels of toll-like receptor 4 (TLR4) signaling transduction and apoptotic pathways were determined by immunocytochemical, biochemical, and molecular biological technologies. In addition, the maturation of dendritic cells (DCs) that were co-cultured in supernatant of FaDu cells was evaluated by flow cytometry to investigate alterations in immune system function. For mechanistic exploration, TLR4 siRNA, p38 siRNA, c-Jun N-terminal kinase (JNK) siRNA, and p65 siRNA were used as loss-of-function target evaluation of tilianin therapy. Combined, these results showed that tilianin treatment increased cytotoxicity as well as the apoptotic population of FaDu cells in a dose-dependent manner. Furthermore, tilianin treatment decreased the level of anti-apoptotic markers Bcl-2 and Bcl-xL, increased the level of apoptotic factors Bad and Bax, and stimulated cytochrome c release, caspase-3 and poly ADP ribose polymerase (PARP) activation in FaDu cells. Furthermore, our findings indicated that tilianin treatment activated TLR4/p38/JNK/NF-κB signaling pathways and increased the release of inflammatory cytokines. This promoted the maturation of DCs to enhance immune system function in the tumor microenvironment. Moreover, the effects of tilianin on immune system function were abolished by TLR4 siRNA and p65 siRNA. In conclusion, these findings suggested that tilianin may be of immunotherapeutic value for inhibiting human pharyngeal squamous cell carcinoma.

ECT2 Increases the stability of EGFR and Tumorigenicity by Inhibiting Grb2 Ubiquitination in Pancreatic Cancer.

The poor prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) is associated with the invasion and metastasis of tumor cells. Epithelial cell transforming 2 (ECT2) is a guanine nucleotide exchange factor (GEF) of the Rho family of GTPases. It has also been reported that upregulation of ECT2 in pancreatic cancer, but the role and mechanism of ECT2 have not been previously determined. We found that ECT2 was significantly elevated in PDAC tissues and cells, correlated with more advanced AJCC stage, distant metastases, and overall survival of patients with PDAC. Inhibition and overexpression tests showed that ECT2 promoted proliferation, migration and invasion in vitro, and promoted tumor growth and metastasis in vivo. We determined that ECT2 was involved in the post-translational regulation of Grb2. ECT2 inhibited the degradation of Grb2 through deubiquitination. Furthermore, knockdown of ECT2 downregulated EGFR levels by accelerating EGFR degradation. EGF stimulation facilitated the formation of ECT2-Grb2 complex. Overall, our findings indicated that ECT2 could be used as a promising new therapeutic candidate for PDAC.

miR193b Promotes Apoptosis of Gastric Cancer Cells via Directly Mediating the Akt Pathway.

Gastric cancer (GC) is one of the most common and fatal malignancies worldwide. MicroRNAs (miRNAs) play a critical role in tumor initiation, proliferation, and metastasis of gastric cancer. miR193b has been identified as a tumor suppressor in a variety of tumor types; however, its role in gastric cancer is yet to be determined. Here, we found a significant downregulation of miR193b expression in both human gastric cancer tissues (p < 0.05) and human gastric cancer cell lines (p < 0.01). Furthermore, the expression level of miR193b correlated with the tumor type, tumor size, and clinical stage (p < 0.05). In vitro, miR193b overexpression inhibited cell survival and induced apoptosis in GC cell lines, indicating that miR193b plays a role in the development of gastric cancer. KRAS was verified as the target of miR193b, and KRAS overexpression attenuated miR193b-induced apoptosis (p < 0.05). Moreover, we found that the Akt pathway negatively regulated miR193b, also affecting apoptosis. Further analyses indicated that PIK3CA mutation and KRAS amplification are two mutually exclusive pathways (p < 0.01), and we hypothesize that both two pathways could result in the carcinogenic overactivation of KRAS. Thus, our results suggest that the Akt-miR193b-KRAS axis may act as a mechanism affecting apoptosis in gastric cancer cells.

Intracellular matrix Gla protein promotes tumor progression by activating JAK2/STAT5 signaling in gastric cancer.

Matrix Gla protein (MGP) has been widely reported as an extracellular matrix protein with abnormal expression in various types of cancer. However, the function of intracellular MGP in gastric cancer (GC) cells remains largely unknown. Here, we demonstrated aberrantly high expression of intracellular MGP in GC as compared to adjacent normal tissues by immunohistochemistry. Moreover, The Cancer Genome Atlas (TCGA) dataset analysis suggested a positive correlation between MGP overexpression and unfavorable prognosis. MGP silencing reduced cell proliferation, migration, invasion, and survival in GC cell lines. Gene set enrichment analysis of TCGA dataset indicated significant enrichment of the IL2-STAT5 signaling in MGP-high GC patients. Immunofluorescence staining and immunoprecipitation showed that MGP binds to p-STAT5 in the nuclei of GC cells. Furthermore, ChIP-qPCR and luciferase reporter assays indicated that MGP acts as a transcriptional co-activator through the enhancement of STAT5 binding to target gene promoters. Use of STAT5 inhibitor revealed that the oncogenic functions of intracellular MGP mainly depend on the JAK2/STAT5 signaling pathway. Taken together, our results indicate that intracellular MGP promotes proliferation and survival of GC cells by acting as a transcriptional co-activator of STAT5. The detected aberrant, high MGP expression in GC tissues highlights MGP as a potential new prognostic biomarker in patients with GC.

MGP Promotes Colon Cancer Proliferation by Activating the NF-κB Pathway through Upregulation of the Calcium Signaling Pathway.

Matrix Gla protein (MGP), an extracellular matrix protein, is mainly associated with the inhibition of calcification in skeleton, coronary artery, and kidney, and more recently it has also been implicated in cancer. However, the biological function of MGP inside cancer cells and its role in colon cancer (CC) remain largely unknown. MGP expression and its association with clinicopathologic characteristics in CC were analyzed by immunohistochemistry and verified by Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets. The effects of MGP on CC cell proliferation were evaluated via knockdown and overexpression experiments in vitro. Mechanisms of MGP in CC were explored by western blots, quantitative real-time PCR, Fluo-3 AM staining, Rhod-2 AM staining, immunofluorescence, and other techniques. Our study confirmed that MGP was upregulated in different stages of CC and associated with a worse prognosis. MGP could enrich intracellular free Ca2+ concentration and promote nuclear factor κB (NF-κB)/p65 phosphorylation, activating the expression of c-MYC, ICAM-1, and VEGFA. Furthermore, the reduction of intracellular free Ca2+ concentration and the subsequent growth inhibition effect on CC cells induced by small interfering RNA targeting MGP (siMGP) could be rescued by a higher calcium concentration environment. Therefore, MGP promotes the growth and proliferation of CC cells by enriching intracellular calcium concentration and activating the NF-κB pathway, and it could serve as a potential prognostic biomarker in CC patients.

miR-92a-3p promotes the proliferation, migration and invasion of esophageal squamous cell cancer by regulating PTEN.

Esophageal squamous cell cancer (ESCC) has a high mortality rate. MicroRNA (miR)­92a­3p is considered to be a tumor promotor and an oncomiR. The aim of the present study was to investigate the effect of miR­92a­3p and its target gene on ESCC in terms of proliferation, migration and invasion. Higher expression of miR­92a­3p was detected in the tissues of patients with ESCC, compared with that in normal tissues. In addition, ESCC cell lines had a higher expression of miR­92a­3p compared with normal esophageal cells. A miR­92a­3p mimic was found to promote ESCC cell proliferation and a miR­92a­3p inhibitor was found to reduce ESCC cell proliferation. miR­92a­3p mimic transfection accelerated ESCC cell migration and invasion and decreased ESCC cell apoptosis via the Bax/Bcl­2 pathway and cleaved caspase­3. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was detected as a target of miR­92a­3p by a dual luciferase reporter assay. The overexpression of PTEN not only inhibited ESCC proliferation, migration and invasion, but also promoted ESCC cell apoptosis. PTEN and the miR­92a­3p mimic inhibited and promoted ESCC proliferation, respectively, which may be associated with the PI3K/Akt pathway. The results of the study revealed that miR­92a­3p promoted the proliferation, migration and invasion of ESCC, and the effect of miR­92a­3p on ESCC was realized by regulating PTEN.

MicroRNA-193b acts as a tumor suppressor gene in human esophageal squamous cell carcinoma via target regulation of KRAS.

In recent years, microRNA-193b (miR-193b) is regarded as a tumor suppressor in the development and progression of various cancers. Several studies have indicated that KRAS could be regulated by miR-193b in pancreatic cancer cells. However, the function of miR-193b in human esophageal squamous cell carcinoma has not been explored intensively thus far. Herein, the relationship between miR-193b and KRAS was mainly explored in esophageal squamous cell carcinoma cells. In the present study, the expression levels of miR-193b and KRAS were assessed in both human esophageal cancer cells and tissues. The direct regulatory relationship between miR-193b and KRAS was evaluated using dual-luciferase assay. The effect of miR-193b overexpression and inhibitor on cell proliferation, migration/invasion, and apoptosis was further detected herein. Our results indicated that the expression of miR-193b was significantly lower in human esophageal cancer tissues than paracancerous tissues. The expression level of miR-193b/KRAS was stage-dependent in human esophageal cancers. KRAS was indicated as the direct target of miR-193b, and upregulation of miR-193b increased the percentage of cell apoptosis, and suppressed cell proliferation as well as cell migration/invasion via direct regulation of KRAS. Therefore, our study indicated that miR-193b plays an important role in the development and progression of human esophageal squamous cell carcinoma, which may become a novel target in the treatment of human esophageal squamous cell carcinoma in the future.