E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET. Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-MET. Significance: This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes.</p

MiR-592 Promotes Gastric Cancer Proliferation, Migration, and Invasion Through the PI3K/AKT and MAPK/ERK Signaling Pathways by Targeting Spry2

Background/Aims: Gastric cancer (GC) is one of the most prevalent digestive malignancies. MicroRNAs (miRNAs) are involved in multiple cellular processes, including oncogenesis, and miR-592 itself participates in many malignancies; however, its role in GC remains unknown. In this study, we investigated the expression and molecular mechanisms of miR-592 in GC. Methods: Quantitative real-time PCR and immunohistochemistry were performed to determine the expression of miR-592 and its putative targets in human tissues and cell lines. Proliferation, migration, and invasion were evaluated by Cell Counting Kit-8, population doubling time, colony formation, Transwell, and wound-healing assays in transfected GC cells in vitro. A dual-luciferase reporter assay was used to determine whether miR-592 could directly bind its target. A tumorigenesis assay was used to study whether miR-592 affected GC growth in vivo. Proteins involved in signaling pathways and the epithelial–mesenchymal transition (EMT) were detected with western blot. Results: The ectopic expression of miR-592 promoted GC proliferation, migration, and invasion in vitro and facilitated tumorigenesis in vivo. Spry2 was a direct target of miR-592 and Spry2 overexpression partially counteracted the effects of miR-592. miR-592 induced the EMT and promoted its progression in GC via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2. Conclusions: Overexpression of miR-592 promotes GC proliferation, migration, and invasion and induces the EMT via the PI3K/AKT and MAPK/ERK signaling pathways by inhibiting Spry2, suggesting a potential therapeutic target for GC

Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis

Dietary iron intake and systemic iron balance are implicated in colorectal cancer (CRC) development, but the means by which iron contributes to CRC are unclear. Gene expression and functional studies demonstrated that the cellular iron importer, divalent metal transporter 1 (DMT1), is highly expressed in CRC through hypoxia-inducible factor 2alpha-dependent transcription. Colon-specific Dmt1 disruption resulted in a tumor-selective inhibitory effect of proliferation in mouse colon tumor models. Proteomic and genomic analyses identified an iron-regulated signaling axis mediated by cyclin-dependent kinase 1 (CDK1), JAK1, and STAT3 in CRC progression. A pharmacological inhibitor of DMT1 antagonized the ability of iron to promote tumor growth in a CRC mouse model and a patient-derived CRC enteroid orthotopic model. Our studies implicate a growth-promoting signaling network instigated by elevated intracellular iron levels in tumorigenesis, offering molecular insights into how a key dietary component may contribute to CRC

Geographic, gender and seasonal variation of diabetes: a nationwide study among 1.4 million participants.

China experienced a rapid increase in the prevalence of diabetes. To assess the prevalence of diabetes among Chinese adults who attend preventive physical examination, and analyzed geographical and gender difference in seasonal variation of fasting blood glucose (FBG). The study used data from 1,390,088 participants attending preventive health examination at 430 health screening centers in 220 cities. Diagnosis of diabetes and prediabetes were based on FBG and hemoglobinA1c and self-report physician's diagnosis. We calculated age and sex standardized prevalence of diabetes according to the sixth Chinese population census data in 2010. Geographical distribution of diabetes and prediabetes were displayed on the country map. FBG were analyzed to detect the seasonal variation adjusted for age and gender by geographic location. The standardized prevalence of diabetes was 8.70% (95% CI, 8.22%-9.19%), 10.7% in men and 6.61% in women. Among those with diabetes, 43.7% (95% CI, 40.9%-46.5%) were aware of their conditions and 38.5% (95% CI, 36.0%-41.1%) were treated. Only 49.3% (95% CI, 47.0%-51.6%) of treated patients achieved glycemic control. The mean level of FBG was higher in winter than summer and in the northern than the southern. The prevalence of diabetes was high whilst the percentages of awareness, treatment and glycemic control were low among adults. Effective measures are needed to prevent and manage diabetes in China. Geographic and seasonal variation of diabetes should be considered for its prevention and control

Size Effects of Au/Ni-Coated Polymer Particles on the Electrical Performance of Anisotropic Conductive Adhesive Films under Flexible Mechanical Conditions

In soft electronics, anisotropic conductive adhesive films (ACFs) are the trending interconnecting approach due to their substantial softness and superior bondability to flexible substrates. However, low bonding pressure (≤1 MPa) and fine-pitch interconnections of ACFs become challenging while being extended in advanced device developments such as wafer-level packaging and three-dimensional multi-layer integrated circuit board assembly. To overcome these difficulties, we studied two types of ACFs with distinct conductive filler sizes (ACF-1: ~20 μm and ACF-2: ~5 μm). We demonstrated a low-pressure thermo-compression bonding technique and investigated the size effect of conductive particles on ACF’s mechanical properties in a customized testing device, which consists of flexible printing circuits and Flex on Flex assemblies. A consistency of low interconnection resistance (<1 Ω) after mechanical stress (cycling bending test up to 600 cycles) verifies the assembly’s outstanding electrical reliability and mechanical stability and thus validates the great effectiveness of the ACF bonding technique. Additionally, in numerical studies using the finite element method, we developed a generic model to disclose the size effect of Au/Ni-coated polymer fillers in ACF on device reliability under mechanical stress. For the first time, we confirmed that ACFs with smaller filler particles are more prone to coating fracture, leading to deteriorated electrical interconnections, and are more likely to peel off from substrate electrode pads resulting in electrical faults. This study provides guides for ACF design and manufacturing and would facilitate the advancement of soft wearable electronic devices

Placental Malfunction, Fetal Survival and Development Caused by Sow Metabolic Disorder: The Impact of Maternal Oxidative Stress

The energy and metabolic state of sows will alter considerably over different phases of gestation. Maternal metabolism increases dramatically, particularly in late pregnancy. This is accompanied by the development of an increase in oxidative stress, which has a considerable negative effect on the maternal and the placenta. As the only link between the maternal and the fetus, the placenta is critical for the maternal to deliver nutrients to the fetus and for the fetus’ survival and development. This review aimed to clarify the changes in energy and metabolism in sows during different pregnancy periods, as well as the impact of maternal oxidative stress on the placenta, which affects the fetus’ survival and development