Circ_0030998 Restrains Cisplatin Resistance Through Mediating miR-1323/PDCD4 Axis in Non-small Cell Lung Cancer.

We aimed to explore the underlying mechanism behind the cisplatin (DDP) resistance of non-small cell lung cancer (NSCLC) cells to identify novel potential therapeutic targets to overcome chemoresistance. Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were applied to analyze RNA and protein expression, respectively. Cell Counting Kit-8 (CCK8) assay was conducted to analyze the DDP resistance of NSCLC cells. Colony formation assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay were performed to analyze cell proliferation ability. Flow cytometry was applied to assess cell apoptosis. Cell migration and invasion were assessed by transwell assays. Cell glycolytic metabolism was analyzed using commercial kits. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to test the intermolecular target relations. Circular RNA_0030998 (circ_0030998) was down-regulated in DDP-resistant NSCLC tissues and cell lines. Circ_0030998 overexpression restrained the DDP resistance, proliferation, migration, invasion and glycolytic metabolism and triggered the apoptosis of NSCLC cells. Circ_0030998 overexpression contributed to the anti-tumor effect of DDP in the growth of xenograft tumor in vivo. MicroRNA-1323 (miR-1323) was a molecular target of circ_0030998 in NSCLC cells. Circ_0030998 overexpression-mediated effects on the DDP resistance and malignant properties of NSCLC cells were largely based on its negative regulation of miR-1323. MiR-1323 interacted with programmed cell death 4 (PDCD4). Circ_0030998 positively regulated PDCD4 expression partly through sponging miR-1323. MiR-1323 silencing restrained DDP resistance and progression of NSCLC partly through up-regulating PDCD4. Circ_0030998 suppressed DDP resistance and NSCLC progression depending on the regulation of miR-1323/PDCD4 axis.

KDF1 Promoted Proliferation and Metastasis of Epithelial Ovarian Cancer via Wnt/Beta-Catenin Pathway: TCGA-Based Data Mining and Experimental Validation.

Objectives: It has been reported that keratinocyte differentiation factor 1 (KDF1) was related to proliferation, differentiation, and cell cycle. However, the role of KDF1 has not been reported in ovarian cancer. The present study investigated the function and the potential mechanism of KDF1 in ovarian cancer. Methods: We evaluated the prognostic value in ovarian cancer based on data from the Cancer Genome Atlas (TCGA) database. The Kruskal-Wallis test, Wilcoxon signed-rank test, and logistic regression were used to evaluate the relationship between KDF1 expression and clinicopathologic features. The Cox regression and the Kaplan-Meier method were adopted to evaluate prognosis-related factors. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) gene enrichment analysis, and Gene Set Enrichment Analysis (GSEA) were performed to identify the key biological process related to KDF1. Then the expression of KDF1 in ovarian cancer tissues was validated by streptavidin-peroxidase (SP) immunohistochemistry. The proliferation and invasion ability of KDF1 were determined by EdU and Transwell assay, respectively, with KDF1 gene silencing and overexpression. The mRNA expression of KDF1 was determined by qPCR. The protein expression of KDF1 was determined using the Western blot. Methods: By performing differential expression analysis on the ovarian cancer data of the TCGA database, it was found that KDF1 is highly expressed in ovarian cancer patients and associated with poorer overall survival (OS) and progression-free survival (PFS) of ovarian cancer patients. The highly expressed KDF1 may reduce cell adhesion according to GO, KEGG, and GSEA results. After analysis combining the relevant clinical features, we found that the high expression of KDF1 is an independent prognostic factor of ovarian cancer and associated with platinum resistance and tumor metastasis in ovarian cancer. At the same time, the BioGRID database showed that there might be protein-protein interaction between KDF1 and E-cadherin. Then we further validated that the high expression of KDF1 had a close correlation with the stage and grade of ovarian cancer in ovarian cancer tissue chips. Silencing KDF1 inhibited the proliferation and invasion ability of SKOV3 cells. By contrast, ectopic expression of KDF1 promoted the proliferation and invasion ability of A2780 cells. We also found that KDF1 can interact with E-cadherin and regulate the expression of Wnt5A and ß-catenin, hence activating Wnt/ß-catenin pathway via in vitro and vivo experiments. Conclusions: Based on the bioinformatics analysis, in vitro experiments, and an in vivo study, it is indicated that KDF1 played an important role in ovarian cancer progression and might be a therapeutic target for patients with ovarian cancer.

Tumor-derived extracellular vesicles inhibit HGF/c-Met and EGF/EGFR pathways to accelerate the radiosensitivity of nasopharyngeal carcinoma cells via microRNA-142-5p delivery.

Radioresistance prevails as one of the largest obstacles in the clinical treatment of nasopharyngeal carcinoma (NPC). Meanwhile, tumor-derived extracellular vesicles (TEVs) possess the ability to manipulate radioresistance in NPC. However, its mechanism remains to be further explored. Therefore, the current study set out to explore the mechanism of microRNA (miR)-142-5p delivered by TEVs in regard to the radiosensitivity of NPC. Firstly, peripheral blood samples were collected from patients with radioresistance and radiosensitivity, followed by RT-qPCR detection of miR-142-5p expression. A dual-luciferase reporter assay was carried out to elucidate the targeting relationship of miR-142-5p with HGF and EGF. In addition, radiotherapy-resistant NPC cell models were established by screening NPC cells with gradient increasing radiation exposure, and co-incubated with EVs isolated from miR-142-5p mimic-transfected NPC cells, followed by overexpression of HGF and EGF. Moreover, cell viability was detected by means of MTS, cell proliferation with a colony formation assay, cell apoptosis with flow cytometry, and expression patterns of related genes with the help of Western blot analysis. NPC xenotransplantation models in nude mice were also established by subcutaneous injection of 5-8FR cells to determine apoptosis, tumorigenicity, and radiosensitivity in nude mice. It was found that miR-142-5p was poorly expressed in peripheral blood from NPC patients with radioresistance. Mechanistic experimentation illustrated that miR-142-5p inversely targeted HGF and EGF to inactivate the HGF/c-Met and EGF/EGFR pathways, respectively. NPC cell apoptosis was observed to be augmented, while their radioresistance and proliferation were restricted by EVs-miR-142-5p or HGF silencing, or EGF silencing. Furthermore, EVs-miR-142-5p inhibited growth and radioresistance and accelerated the apoptosis of radiotherapy-resistant NPC cells in nude mice by inhibiting the HGF/c-Met and EGF/EGFR pathways. Collectively, our findings indicated that TEVs might inhibit the HGF/c-Met and EGF/EGFR pathways by delivering miR-142-5p into radiotherapy-resistant NPC cells to enhance radiosensitivity in NPC.

DNTTIP1 is a Prognostic Biomarker Correlated With Immune Infiltrates in Hepatocellular Carcinoma: A Study Based on The Cancer Genome Atlas Data.

Deoxynucleotidyltransferase terminal-interacting protein 1 (DNTTIP1) is involved in the deacetylation of p53 in regulating cell cycle and is associated with cancers at the molecular level. In this study, we evaluated the prognostic value in hepatocellular carcinoma (HCC) based on data from The Cancer Genome Atlas (TCGA) database. Kruskal-Wallis test, Wilcoxon signed-rank test, and logistic regression were used to evaluate the relationship between DNTTIP1 expression and clinicopathological features. Cox regression and the Kaplan-Meier method were adopted to evaluate prognosis-related factors. Gene set enrichment analysis (GSEA) was performed to identify the key pathways related to DNTTIP1. The correlations between DNTTIP1 and cancer immune infiltrates were investigated by single-sample Gene Set Enrichment Analysis (ssGSEA). DNTTIP1 was found to be upregulated with amplification in tumor tissues in multiple HCC cohorts. High DNTTIP1 expression was associated with poorer overall survival (OS) and disease-free survival (DFS). GSEA suggested that DNTTIP1 regulates the cell cycle mitotic, G1/S, and G2/M phases and Fc fragment of IgE receptor I (FCERI)-mediated NF-κB and MAPK pathway and Fc fragment of IgG receptor (FCGR) activation pathways. Notably, ssGSEA indicated that DNTTIP1 expression was positively correlated with infiltrating levels of Th2 cells, Tfh, NK CD56 bright cells, aDCs, T helper cells, Th1 cells, and macrophages. These findings suggest that DNTTIP1 is correlated with prognosis and immune infiltration in HCC, which lays a foundation for further study of the immune-regulatory role of DNTTIP1 in HCC.

Prognostic Biomarker DDOST and Its Correlation With Immune Infiltrates in Hepatocellular Carcinoma.

Background: Dolichyl-diphosphooligosaccharide-protein glycosyltransferase non-catalytic subunit (DDOST) is an important enzyme in the process of high-mannose oligosaccharide transferring in cells. Increasing DDOST expression is associated with impairing liver function and the increase of hepatic fibrosis degrees, hence exacerbating the liver injury. However, the relation between DDOST and hepatocellular carcinoma (HCC) has not been revealed yet. Method: In this study, we evaluated the prognostic value of DDOST in HCC based on data from The Cancer Genome Atlas (TCGA) database. The relationship between DDOST expression and clinical-pathologic features was evaluated by logistic regression, the Wilcoxon signed-rank test, and Kruskal-Wallis test. Prognosis-related factors of HCC including DDOST were evaluated by univariate and multivariate Cox regression and the Kaplan-Meier method. DDOST-related key pathways were identified by gene set enrichment analysis (GSEA). The correlations between DDOST and cancer immune infiltrates were investigated by the single-sample gene set enrichment analysis (ssGSEA) of TCGA data. Results: High DDOST expression was associated with poorer overall survival and disease-specific survival of HCC patients. GSEA suggested that DDOST is closely correlated with cell cycle and immune response via the PPAR signaling pathway. ssGSEA indicated that DDOST expression was positively correlated with the infiltrating levels of Th2 cells and negatively correlated with the infiltration levels of cytotoxic cells. Conclusion: All those findings indicated that DDOST was correlated with prognosis and immune infiltration in HCC.

Erenumab safety and efficacy in migraine: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Erenumab is a new medicine recently approved in the United States of America for the preventive treatment of migraine among adults. We aimed to conduct a meta-analysis and evaluation of the efficacy and safety of erenumab among patients with migraine. METHODS: The electronic databases that were searched comprised PubMed, Embase and the Cochrane library, which were independently retrieved by 2 reviewers. Only randomized controlled trials (RCTs) that compared placebo with erenumab were selected. Mean differences (MDs), pooled risk ratios (RRs), and their corresponding 95% confidence intervals (CIs) were calculated for continuous and dichotomous data, respectively. RESULTS: Five RCTs representing 2928 patients were included. Pooled analysis showed significant reductions in the 50% responder rate (RR 1.55; P < .00001; I = 49%). In addition, the mean monthly migraine days from baseline in the erenumab group compared with placebo (MD-1.32; P < .00001; I = 100%) and migraine-specific medication days) from baseline (MD-1.41; P < .00001; I = 100%) were significantly decreased for the erenumab group as compared with placebo. Furthermore, Migraine-specific medication days from baseline in the 140 mg erenumab group were significantly reduced as compared the 70 mg group (MD = 0.55; P < .00001; I = 90%). Finally, there was no significant difference between the erenumab group and placebo for any adverse event and serious adverse event. CONCLUSION: Among patients with migraine, both 70 and 140 mg of erenumab were associated with reduced Migraine-specific medication days, Migraine-specific medication days from baseline, and an increased rate of a 50% reduction, in the absence of an increased risk of any serious adverse effect.