Inhibition of USP21 leads to ovarian carcinoma cell death by suppressing MAPK signaling.

Ovarian cancer is the most aggressive and lethal of all gynecologic malignancies. Although the overexpression (OE) of ubiquitin-specific peptidase 21 (USP21) has been observed in multiple cancers, its expression profile and biological function in ovarian cancer remain unknown. The expression levels of USP21 in ovarian cancer cells and tissues as well as adjacent normal tissues were assessed by qRT-PCR or Western blot assay. The biological function of USP21 in ovarian cancer cells was assessed by cell growth assay in vitro and a tumor growth model in vivo. Our study revealed that USP21 was markedly elevated in ovarian carcinoma tissues compared with adjacent normal tissues. Downregulation of USP21 attenuated the expression levels of MEK2 and p-ERK1/2. Depletion of USP21 resulted in suppressed cell growth of ovarian cancers in vitro and inhibited tumor growth in vivo. Conversely, OE of USP21 promoted the cell proliferation of ovarian cancers and conferred resistance to BAY 11-7082. These findings provide evidences supporting the notion of USP21 as a promising therapeutic target for the treatment of ovarian cancer.

Iridoid Glycoside Cornuside Alleviates the Symptom of Gestational Diabetes Mellitus by Suppressing Inflammation and Regulating Beta Cell Function.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a frequently occurring complication during pregnancy and has adverse effects on both mother and offspring. ß-Cell dysfunction and inflammation play important roles in GDM pathogenesis. Cornuside (CNS) is an iridoid glycoside that exhibits anti-inflammation activities. In the present study, we explored the effects of CNS on ß-cell and GDM. DESIGN: MIN6 ß-cell line cells were treated with varying concentrations of CNS. The content and secretion of insulin were measured. METHODS: The expression of Pdx1, Rac1, Piezo, and NeuroD1 and cell proliferation in CNS-treated MIN6 cells were detected. CNS was administered to GDM mice, and the symptoms of GDM, expression of IL-6 and TNF-α, and activation of NF-κB in GDM mice were measured. RESULTS: CNS promoted cell proliferation of MIN6 cells, enhanced insulin content and secretion, and expression of Pdx1, Rac1, Piezo, and NeuroD1 in MIN6 cells. CNS alleviated symptoms of GDM mice and decreased serum levels of IL-6 and TNF-α in GDM mice. CNS suppressed the expression of IL-6 and TNF-α, as well as the activation of NF-κB in the placenta of GDM mice. CONCLUSION: CNS ameliorates GDM symptoms by suppressing inflammation and enhancing ß-cell functions.

TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin.

We aimed to investigate the effects of tumor necrosis factor (TNF)-α on the expression of interferon α/ß receptor subunit 1 (IFNAR1) and cervical squamous cancer (CSCC) resistance to Cisplatin, as well as the underlying mechanisms. Kaplan-Meier analysis was used to plot the overall survival curves. SiHa cells were treated with 20 ng/ml TNF-α to determine cell proliferation in human CSCC cells and the expression of IFNAR1. The effects of TNF-α on the downstream signaling pathway, including casein kinase 1α (CK1α), were investigated using the caspase protease inhibitor FK009, the c-Jun kinase inhibitor SP600125, and the nuclear factor kappa-B inhibitor ammonium pyrrolidinedithiocarbamate (PDTC). TNF-α induced down-regulation of IFNAR1 in human CSCC cells and promoted proliferation of SiHa cells. SiHa cells were transfected with the catalytic inactive mutant CK1α K49A, and the ability of TNF-α to induce down-regulation of IFNAR1 expression was found to be significantly diminished in this context. FK009 and PDTC had no obvious effect on the expression of CK1α, however, SP600125 significantly reduced the expression of CK1α in the presence of TNF-α. SiHa cells treated with TNF-α showed reduced sensitivity to Cisplatin and exhibited higher cell viability, while the sensitivity of SiHa cells to Cisplatin was restored after treatment with CK1α inhibitor D4476. Additionally, we constructed a TNF-α overexpressing SiHa cell line and a transplanted tumor model. The results were similar to those of in vitro efficacy. We demonstrate that TNF-α-induced down-regulation of type I interferon receptor contributes to acquired resistance of cervical squamous cancer to Cisplatin.

The cadherin protein CDH19 mediates cervical carcinoma progression by regulating AKT/NF-κB signaling.

The cell adhesion protein cadherin 19 (CDH19) has been reported to be involved in various types of cancer, but its role in cervical carcinoma remains unknown. We collected and analyzed the patients' data using the GEPIA Kaplan-Meier plotter databases. CDH19 was overexpressed in cervical carcinoma cells to assess its effect on cell proliferation and activation of AKT and NF-κB signaling pathways. A xenograft mouse model was established to study the function of CDH19 in vivo. We found that CDH19 expression was significantly downregulated in cervical carcinoma tissues compared to adjacent normal tissues. Patients with high expression of CDH19 had a significantly better overall survival rate than those with low CDH19 expression. CDH19 expression was negatively correlated with the expression of the proliferation marker Ki-67, and overexpression of CDH19 significantly inhibited cervical carcinoma cell proliferation. Furthermore, overexpression of CDH19 suppressed the activation of the AKT and NF-κB signaling pathways, and CDH19-overexpressing cervical carcinoma tumors exhibited significantly slower growth in vivo. CDH19 plays an important role in cervical carcinoma by suppressing both cell proliferation and the activation of AKT and NF-κB signaling pathways. Therefore, CDH19 may be a potential therapeutic target for cervical carcinoma.

How Do Chinese National Scenic Areas Affect Tourism Economic Development? The Moderating Effect of Time-Limited Rectification.

Based on panel data on 124 prefecture-level and above cities from 2003 to 2018, this study investigated the impact of CNSAs on tourism economic development and the moderating effect of time-limited rectification by comprehensively using the quasi-DID model, the static spatial Durbin model, and the dynamic spatial Durbin model. The results showed that the impact of CNSAs on tourism economic development has a heterogeneous characteristic in terms of tourists and revenue. In addition, the spatial spillover effect and the path dependence have effectively promoted tourism economic development. Furthermore, the effectiveness of time-limited rectification has been proved in this study, while the "beggar-thy-neighbor" effect has, to some extent, weakened the promotional effect of CNSAs on tourism economic development, especially in terms of international tourists and international tourism revenue. Finally, relevant policy implications for the superior department in charge, local governments, and the management department of CNSAs are outlined to provide a practical reference for promoting the high-quality development of the tourism economy in China.

Establishing and Validating an Aging-Related Prognostic Four-Gene Signature in Colon Adenocarcinoma.

BACKGROUND: Aging is a process that biological changes accumulate with time and lead to increasing susceptibility to diseases like cancer. This study is aimed at establishing an aging-related prognostic signature in colon adenocarcinoma (COAD). METHODS: The transcriptome data and clinical variables of COAD patients were downloaded from TCGA database. The genes in GOBP_AGING gene set was used for prognostic evaluation by the univariate and multivariate Cox regression analyses. The model was presented by a nomogram and assessed by the Kaplan-Meier curves and calibration curves. The drug response and gene mutation were also performed to implicate the clinical significance. The GO and KEGG analyses were employed to unravel the potential functional mechanism. RESULTS: The Gene Set Enrichment Analysis result indicates that GOBP_AGING pathway is significantly enriched in COAD samples. Four aging-related genes are finally used to construct the aging-related prognostic signature: FOXM1, PTH1R, KL, and CGAS. The COAD patients with high risk score have much shorter overall survival in both train cohort and test cohort. The nomogram is then assembled to predict 1-year, 3-year, and 5-year survival. Patients with high risk score have elevated infiltrating B cell naïve and attenuated cisplatin sensitivity. The mutation landscape shows that the TTN, FAT4, ZFHX4, APC, and OBSCN gene mutation are different between high risk score patients and low risk score patients. The differentially expressed genes between patients with high score and low score are enriched in B cell receptor signaling pathway. CONCLUSION: We constructed an aging-related signature in COAD patients, which can predict oncological outcome and optimize therapeutic strategy.

MicroRNA-625-5p Sponges lncRNA MALAT1 to Inhibit Cervical Carcinoma Cell Growth by Suppressing NF-κB Signaling.

The exact expression profile and potential involvement of miR-625-5p in the tumor biology of cervical carcinoma are still elusive. In this study, we aimed to analyze the expression status and possible involvements of miR-625-5p in both clinical tissue samples and cell culture of cervical carcinoma. The relative expression levels of miR-625-5p and NF-κB transcript were determined by real-time polymerase chain reaction. Cell proliferation was measured using Cell Counting Kit-8. The protein levels of Cyclin D1, CDK4, NF-κB, and GAPDH were examined by Western blotting. The regulatory effects of miR-625-5p on NF-κB and MALAT1 were interrogated by luciferase reporter assay. We demonstrated that miR-625-5p was downregulated and predicted better survival in cervical carcinoma. Ectopic over-expression of miR-625-5p inhibited cell growth via targeting NF-κB. We further identified MALAT1 as the competitive endogenous long non-coding RNA for miR-625-5p, and over-expression of MALAT1 attenuated the inhibitory effect of miR-625-5p on NF-κB signaling in cervical carcinoma. Our study characterized the suppressive expression of miR-625-5p in cervical carcinoma and unraveled the importance of MALAT1/miR-625-5p/NF-κB signaling in this disease.