Long non-coding RNA MIR22HG inhibits the proliferation and migration, and promotes apoptosis by targeting microRNA-9-3p/ SOCS1 axis in small cell lung cancer cells.

BACKGROUND: This study aims to determine the role of long non-coding RNA (LncRNA) MIR22HG in small cell lung cancer (SCLC), and to explore its relevant mechanism. METHODS AND RESULTS: The expressions of genes and proteins in SCLC cells were examined applying qRT-PCR and western blot. Cell proliferation estimation was implemented utilizing cell counting kit-8 (CCK-8) and colony formation assays; the assessment of cell migration and invasion was operated employing Wound healing and Transwell; apoptosis evaluation was conducted adopting flow cytometric assay. Binding relationships was confirmed by luciferase reporter assay. Moreover, SCLC animal model was established to explore the role of MIR22HG in vivo. It was found that MIR22HG was declined and miR-9-3p was elevated in five SCLC cell lines (NCI-H446, NCI-H69, SHP-77, DMS79 and NCI-H345) in comparison with normal human bronchial epithelial cell line (NHBE). More interestingly, overexpression of MIR22HG resulted in decreased cell viability, declined colony formation, diminished capacities of cell migration and invasion in NCI-H446 and NCI-H345 cells but induced more apoptotic cells. However, these impacts were reversed by miR-9-3p upregulation. Meanwhile, MIR22HG could bind to miR-9-3p and negatively regulate its expression in SCLC. What's more, LncRNA MIR22HG overexpression was also testified to elevate SOCS1 via downregulating miR-9-3p expression. Furthermore, in vivo study further confirmed the role of MIR22HG/miR-9-3p in tumor regulation of SCLC. CONCLUSIONS: In conclusion, MIR22HG in SCLC was found to modulate miR-9-3p level and might act as a possible biomarker for SCLC treatment.

ß-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes.

Fibroblast growth factor 21 (FGF21) is secreted by hepatocytes as a peptide hormone to regulate glucose and lipid metabolism. FGF21 promotes hepatic ketogenesis and increases ketone body utilization in starvation. Histones are the target molecules of nutrients in regulating hepatic metabolic homeostasis. However, the effect of ketone bodies on FGF21 expression and the involvement of histones in it is not clear yet. The present study observed the effects of ß-hydroxybutyrate (ß-OHB), the main physiological ketone body, on FGF21 expression in human hepatoma HepG2 cells in vitro and in mice in vivo, and the role of histone deacetylases (HDACs) in ß-OHB-regulated FGF21 expression was investigated. The results showed that ß-OHB significantly upregulated FGF21 gene expression and increased FGF21 protein levels while it inhibited HDACs' activity in HepG2 cells. HDACs' inhibition by entinostat upregulated FGF21 expression and eliminated ß-OHB-stimulated FGF21 expression in HepG2 cells. Intraperitoneal injections of ß-OHB in mice resulted in the elevation of serum ß-OHB and the inhibition of hepatic HDACs' activity. Meanwhile, hepatic FGF21 expression and serum FGF21 levels were significantly increased in ß-OHB-treated mice compared with the control. It is suggested that ß-OHB upregulates FGF21 expression through inhibition of HDACs' activity in hepatocytes.

Far upstream element -binding protein 1 (FUBP1) participates in the malignant process and glycolysis of colon cancer cells by combining with c-Myc.

Human distal upstream element (Fuse) binding protein 1 (FUBP1) is a transcriptional regulator of c-Myc and represents an important prognostic marker in many cancers. Therefore, the present study aimed to investigate whether FUBP1 could combine with c-Myc to participate in the progression of colon cancer. Detection of FUBP1 expression was done through reverse transcription-quantitative PCR (RT-qPCR), and the combination of FUBP1 and c-Myc was detected by immunoprecipitation assay. Cell counting kit (CCK)-8, colony formation, transwell and wound healing were applied for assessing the ability of cells to proliferate, migrate, and invade; glycolysis and lactic acid detection kits were used to detect glucose uptake and lactic acid content, while western blotting was adopted to detect the protein expression of glycolysis-related genes. FUBP1 expression was elevated in HCT116 cells relative to other colon cancer cell lines, and silencing FUBP1 could inhibit the ability of HCT116 cells to proliferate, migrate, invade and glycolysis, and enhance its apoptosis. In addition, the results of immunoprecipitation experiments showed that FUBP1 could bind to c-Myc. c-Myc overexpression reversed the inhibitory effects of FUBP1 knockdown on the ability of HCT116 cells to proliferate, migrate, invade and glycolysis. The results indicated that FUBP1 could participate in the deterioration process of colon cancer cells by combining with c-Myc, and it has clinical significance for understanding the key role of FUBP1 in tumor genesis.

Ouabain elicits human glioblastoma cells apoptosis by generating reactive oxygen species in ERK-p66SHC-dependent pathway.

Excessive reactive oxygen species (ROS) generation has been implicated as one of main agents in ouabain-induced anticancer effect. Unfortunately, the signaling pathways under it are not very clarified. In the present study, we investigated the molecular mechanism involved in ouabain-induced ROS generation and cell apoptosis on human U373MG and U87MG glioma cells. Ouabain-induced glioblastoma cells apoptosis and increased ROS generation. Clearance ROS by three different ROS scavenger partly, but not totally, reversed ouabain's effect on cell apoptosis. Ouabain-induced ROS generation was not regulated by calcium overload, reduced nicotinamide adenine dinucleotide phosphate oxidation, but by p66Shc phosphorylation. Ouabain treatment increased p66Shc Ser36 phosphorylation. Knockdown of p66Shc by siRNA significantly inhibited ROS generations in response to ouabain. Ouabain-induced p66Shc phosphorylation through Src/Ras/extracellular signal-regulated kinase signal pathway. Our results uncovered a novel signaling pathway with p66Shc, ouabain-induced ROS generation, and glioblastoma cell apoptosis.

Prognostic value of poorly differentiated clusters in invasive breast cancer.

BACKGROUND: Our study aimed to assess the prognostic value of poorly differentiated clusters (PDCs) in invasive breast cancer. METHODS: A total of 146 cases of operable invasive ductal carcinoma that was not otherwise specified (IDC-NOS), from 2002 to 2009, were pathologically reviewed. Cancer clusters with five or more cancer cells and lacking gland-like structures were counted from a field containing maximum clusters in H & E slides under a×20 objective lens (0.950 mm2 field of vision). RESULTS: Tumors with <5, 5 to 9, and ≥10 clusters were graded as G1, G2, and G3, respectively (n=41, 60, and 45 tumors, respectively). An interobserver test showed good reproducibility, with a Cohen's kappa coefficient of 0.739. The PDC grade was significantly associated with N stage (P<0.001), lymphovascular invasion (P=0.007), tumor budding grade (P<0.001), relapse rate (P<0.001), and death rate (P<0.001). Survival analyses revealed that the PDC grade was a significant prognostic factor for disease-free survival (hazard ratio 3.811; P<0.001) and overall survival (hazard ratio 3.730; P=0.001), independent of T stage, N stage, or tumor budding grade. CONCLUSIONS: The PDC grade is an independent prognostic factor of IDC-NOS. Considering the simplicity and availability of this method relative to conventional clinical pathology, PDCs may serve as a novel prognostic histological characteristic in IDC-NOS.

Hydrogen sulfide protected gastric epithelial cell from ischemia/reperfusion injury by Keap1 s-sulfhydration, MAPK dependent anti-apoptosis and NF-κB dependent anti-inflammation pathway.

Hydrogen sulfide (H2S) has been proposed as a novel gas-transmittter, which plays multiple physiological and pathological functions in various body systems, including gastrointestinal tract. The present study was undertaken to investigate the effects and mechanisms of H2S pharmacological preconditioning on gastric epithelial cells ischemia-reperfusion (I/R) injury. We report here that sodium hydrosulfide (NaHS), an H2S donor, concentration-dependently suppressed I/R-induced cellular injury and apoptotic cell death. This protection effect was also confirmed by endogenous over-producing H2S. Furthermore, NaHS also prevented I/R-induced oxidative stress and inflammatory responses, evidenced by increases in GSH level, decreases in MDA contents, reactive oxygen species generation and secretions of NO, IL-6 and TNF-α. NaHS also prevented I/R-induced p38- and c-Jun NH2-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) phosphorylation and NF-κB activation. H2S also induced Keap1 s-sulfhydration, and further Keap1/Nrf2 disassociation and Nrf2 activation. H2S exerted its protective effect through reactive oxygen species clearance, inhibition of p38 and JNK dependent cell apoptosis and NF-κB dependent inflammation pathway. Our results provide evidence that H2S may have potential therapeutic value in acute gastric mucosal lesion, which is often caused by ischemia/reperfusion.

The prognostic value of tumor budding in invasive breast cancer.

We investigated the prognostic value of tumor budding in 160 cases of operable invasive ductal carcinoma, not otherwise specified (IDC-NOS). The number of buds was counted in H&E slides with a maximal invasive margin in a 0.950mm(2) field of vision (200×). According to a cut-off score selected by ROC analysis, the cohort was dichotomized into a low (0-7 budding foci, 107 cases, 66.9%) and a high-grade budding group (8 or more budding foci, 53 cases, 33.1%). The inter-observer test showed a good reproducibility with 0.717 as the К value. High-grade budding was significantly associated with the presence of lymphovascular invasion (LVI) (P=0.001), larger tumor size (P=0.014), and worse clinical outcome (P<0.001). By immunohistochemical staining, budded cells at the margin displayed epithelial mesenchymal transition (EMT)-like molecular phenotype and decreased proliferative activity. Survival analyses revealed that tumor budding (HR 4.275, P<0.001) together with tumor size (HR 2.468, P=0.002), node status (HR 2.362, P<0.001), and LVI status (HR 1.910, P=0.035) was the independent prognostic factor in IDC-NOS. In conclusion, tumor budding is a reproducible, significant, and independent histopathological prognostic factor in IDC-NOS.