β‐Catenin is a central player in Wnt signaling, and activation of Wnt signaling is associated with cancer development. E‐cadherin in complex with β‐catenin mediates cell–cell adhesion, which suppresses β‐catenin‐dependent Wnt signaling. Recently, a tumor‐suppressive role for E‐cadherin has been reconsidered, as re‐expression of E‐cadherin was reported to enhance the metastatic potential of malignant tumors. To explore the role of E‐cadherin, we established an E‐cadherin‐expressing cell line, EC96, from AGS cells that featured undetectable E‐cadherin expression and a high level of Wnt signaling. In EC96 cells, E‐cadherin re‐expression enhanced cell proliferation, although Wnt signaling activity was reduced. Subsequent analysis revealed that nuclear factor‐κB (NF‐κB) activation and consequent c‐myc expression might be involved in E‐cadherin expression‐mediated cell proliferation. To facilitate rapid proliferation, EC96 cells enhance glucose uptake and produce ATP using both mitochondria oxidative phosphorylation and glycolysis, whereas AGS cells use these mechanisms less efficiently. These events appeared to be mediated by NF‐κB activation. Therefore, E‐cadherin re‐expression and subsequent induction of NF‐κB signaling likely enhance energy production and cell proliferation.

Severe fever with thrombocytopenia syndrome (SFTS), an emerging tick-borne viral disease, is prevalent in East Asia and has also been reported in Southeast Asia since 2019. SFTS patients in Vietnam were first reported in 2019. However, the seroprevalence of severe fever with thrombocytopenia syndrome virus (SFTSV) in Vietnam has not been reported. To investigate the seroprevalence of SFTSV in Vietnam, we collected serum samples from 714 healthy residents in Thua Thien Hue and Quang Nam Province, Vietnam, and the seroprevalence of SFTSV was assessed using immunofluorescence antibody assay (IFA), Enzyme-Linked Immunosorbent Assays (ELISAs) and the 50% focus reduction neutralization test (FRNT50) assay. The seroprevalence of anti-SFTSV IgM or IgG was observed to be 3.64% (26/714), high IgM positivity was >80 (0.28%, 2/714) and the titer of neutralizing antibodies against SFTSV ranged from 15.5 to 55.9. In Pakistan, SFTSV infection confirmed using a microneutralization test (MNT) assay (prevalence is 2.5%) and ELISAs showed a high seroprevalence (46.7%) of SFTSV. Hence, the seroprevalence rate in Vietnam is similar to that in Pakistan and the number of SFTS patients could increase in Vietnam.

Significant progress has been made on the molecular biology of the severe fever with thrombopenia virus (SFTSV); however, many parts of the pathophysiological mechanisms of mortality in SFTS remain unclear. In this study, we investigated virologic and immunologic factors for fatal outcomes of patients with SFTS. We prospectively enrolled SFTS patients admitted from July 2015 to October 2020. Plasma samples were subjected to SFTSV RNA RT-PCR, multiplex microbead immunoassay for 17 cytokines, and IFA assay. A total of 44 SFTS patients were enrolled, including 37 (84.1%) survivors and 7 (15.9%) non-survivors. Non-survivors had a 2.5 times higher plasma SFTSV load than survivors at admission (p < 0.001), and the viral load in non-survivors increased progressively during hospitalization. In addition, non-survivors did not develop adequate anti-SFTSV IgG, whereas survivors exhibited anti-SFTSV IgG during hospitalization. IFN-α, IL-10, IP-10, IFN-γ, IL-6, IL-8, MCP-1, MIP-1α, and G-CSF were significantly elevated in non-survivors compared to survivors and did not revert to normal ranges during hospitalization (p < 0.05). Severe signs of inflammation such as a high plasma concentration of IFN-α, IL-10, IP-10, IFN-γ, IL-6, IL-8, MCP-1, MIP-1α, and G-CSF, poor viral control, and inadequate antibody response during the disease course were associated with mortality in SFTS patients.

Metformin can suppress cell proliferation and viability by altering mitochondrial energy metabolism and by the activation of 5'‑adenosine monophosphate‑activated protein kinase (AMPK). The current study demonstrated that metformin‑induced suppression of cell proliferation is further potentiated by AMPK‑mediated suppression of β‑catenin‑dependent wingless‑type (Wnt) signaling. Treatment with metformin reduced mitochondrial oxidative phosphorylation and glycolysis, leading to an energy imbalance that may induce AMPK phosphorylation in RKO cells. Metformin treatment also decreased β‑catenin expression in the cytoplasm and nucleus. Active AMPK was revealed to be associated with β‑catenin. The decrease in β‑catenin expression was inhibited by proteosome inhibition through phosphorylation of β‑catenin at serine 33/37. Given that nuclear translocation‑associated phosphorylation of β‑catenin at serine was maintained, the association of β‑catenin with AMPK may sequester β‑catenin in the cytoplasm and lead to proteosomal degradation. Furthermore, metformin‑induced suppression of cell proliferation was partially recovered by AMPK inhibition, while metformin inhibited Wnt‑mediated cell proliferation and β‑catenin expression. The present results suggest that AMPK activation can suppress β‑catenin‑dependent Wnt signaling by cytoplasmic sequestering of β‑catenin through AMPK, which further decreases cell proliferation in addition to metformin‑induced mitochondrial dysfunction.

Yes-associated protein (YAP) regulates numerous cellular homeostasis processes and malignant transformation. We found that YAP influences ZO-1-mediated cell migration using E-cadherin-restored EC96 cells derived from gastric malignant AGS cells. Ectopic expression of E-cadherin enhanced straightforward migration of cells, in comparison to the meandering movement of parental AGS cells. In EC96 cells, YAP and ZO-1 expression increased but nuclear YAP levels and activity were reduced. Nuclear factor-κB (NF-κB) mediated the increase in ZO-1 expression, possibly stabilizing cytoplasmic YAP post-translationally. Downregulation of YAP expression using siYAP RNA or stable knock-down inhibited straightforward cell migration by fragmenting ZO-1 containing tight junctions (TJs) but not adherens junctions, implying involvement of YAP in ZO-1-mediated cell migration. The association of YAP with ZO-1 was mediated by angiomotin (AMOT) because downregulation of AMOT dissociated YAP from ZO-1 and reduced cell migration. E-cadherin restoration in malignant cancer cells induced NF-κB signaling to enhance ZO-1 expression and subsequently stabilize YAP. At high expression levels, YAP associates with ZO-1 via AMOT at TJs, influencing ZO-1-mediated cell migration and maintaining TJ integrity.