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The transcriptional coactivator Yes-associated protein (YAP)/transcriptional co-activator with PDZ binding motif (TAZ) induces cell proliferation through nuclear localization at low cell density. Conversely, at extremely high cell density, the Hippo pathway, which regulates YAP/TAZ, is activated. This activation leads to the translocation of YAP/TAZ into the cytoplasm, resulting in cell cycle arrest. Various cancer cells have several times more YAP/TAZ than normal cells. However, it is not entirely clear whether this several-fold increase in YAP/TAZ alone is sufficient to overcome proliferation inhibition (contact inhibition) under high-density conditions, thereby allowing continuous proliferation. In this study, we construct a three-dimensional (3D) mathematical model of cell proliferation incorporating the Hippo-YAP/TAZ pathway. Herein, a significant innovation in our approach is the introduction of a novel modeling component that inputs cell density, which reflects cell dynamics, into the Hippo pathway and enables the simulation of cell proliferation as the output response. We assume such 3D model with cell-cell interactions by solving reaction and molecular dynamics (MD) equations by applying adhesion and repulsive forces that act between cells and frictional forces acting on each cell. We assume Lennard-Jones (12-6) potential with a softcore character so that each cell secures its exclusive domain. We set cell cycles composed of mitotic and cell growth phases in which cells divide and grow under the influence of cell kinetics. We perform mathematical simulations at various YAP/TAZ levels to investigate the extent of YAP/TAZ increase required for sustained proliferation at high density. The results show that a twofold increase in YAP/TAZ levels of cancer cells was sufficient to evade cell cycle arrest compared to normal cells, enabling cells to continue proliferating even under high-density conditions. Finally, this mathematical model, which incorporates cell-cell interactions and the Hippo-YAP/TAZ pathway, may be applicable for evaluating cancer malignancy based on YAP/TAZ levels, developing drugs to suppress the abnormal proliferation of cancer cells, and determining appropriate drug dosages. The source codes are freely available. Author summary: This study numerically clarifies multicellular spatiotemporal properties by solving MD and reaction equations for application to any reaction network. We applied the Hippo-YAP/TAZ signaling pathway as a reaction network model for normal and cancer tissues. Moreover, we quantitatively discuss the cell proliferation outcomes in normal and cancerous tissues by calculating time-dependent multicellular structures on the 3D model using the MD method. This approach paves the way for the mathematical exploration of patterns in physical therapies, such as drug administration. [ABSTRACT FROM AUTHOR]

Simple Summary: Receptor for hyaluronan-mediated motility (RHAMM) is a hyaluronan receptor involved in various functions, including in breast cancer. Chemoresistance in breast cancer is a major clinical issue, and the role of RHAMM and hyaluronan in this process is not well understood. Our study found that RHAMM and hyaluronan are linked to increased aggressiveness and recurrence in breast cancer after chemotherapy. In lab experiments, epirubicin-resistant breast cancer cells had higher RHAMM levels than non-resistant cells. Knockdown of RHAMM decreased the growth and migration of both cell types. It also lowered CD44 levels, a marker of cancer stem cells, and changed N-cadherin and E-cadherin, resulting in more typical epithelial cell behavior. These findings suggest that abnormal RHAMM activity contributes to chemoresistance by enhancing cancer stem cell properties and altering cell characteristics, promoting cancer growth and spread. This research could lead to new ways to combat breast cancer chemoresistance. Background/Objectives: Receptor for hyaluronan-mediated motility (RHAMM) is a hyaluronan (HA) receptor, which exerts diverse biological functions in not only physiological but also pathological conditions in human malignancies, including breast cancer. Although chemoresistance is a significant clinical challenge in breast cancer, a possible contribution of RHAMM and hyaluronan to breast cancer chemoresistance has remained unclear. Methods: We immunolocalized RHAMM and HA in breast carcinoma tissues. Also, we utilized epirubicin-sensitive (parental) and rpirubicin-resistant (EPIR) breast cancer cell lines to explore the role of RHAMMM in breast cancer progression. Results: We found out that RHAMM and HA were cooperatively correlated with breast cancer aggressiveness and recurrence after chemotherapy. In vitro studies demonstrated that RHAMM was overexpressed in EPIR cells compared to parental cells. In addition, the knockdown of RHAMM significantly suppressed proliferation and migration of both parental and EPIR cells. On the other hand, the expression level of cancer stem cell marker CD44, which was overexpressed in M-EPIR (epirubicin-resistant MCF-7 subline) compared to MCF-7, was significantly suppressed by knockdown of RHAMM. In addition, the knockdown of RHAMM significantly altered the expression of N-cadherin and E-cadherin, leading to an epithelial phenotype. Conclusions: Aberrant RHAMM signaling were considered to cause chemoresistance related to cancer stemness and epithelial to mesenchymal transition, and increased cell proliferation and migration of both chemo-sensitive and chemo-resistant breast cancer cells. [ABSTRACT FROM AUTHOR]

Zinc levels in breast cancer tissues have been reported to be higher than those in normal tissues. In addition, the expression levels of zinc transporters, including ZnT5 and ZnT6, are reportedly higher in breast cancer than in normal breast tissues. ZnT5 and ZnT6 also contribute to heterodimer formation and are involved in several biological functions. However, the functions of ZnT5 and ZnT6 heterodimers in breast cancer remain unknown. Therefore, we first investigated the immunolocalization of ZnT5 and ZnT6 in pathological breast cancer specimens and in MCF‐7 and T‐47D breast cancer cells. Next, we used small interfering RNA to assess cell viability and migration in ZnT5 knockdown MCF‐7 and T‐47D cells. Immunohistochemical analysis showed that the number of ZnT5‐positive breast cancer cells was inversely correlated with the pathologic N factor status. ZnT5 knockdown had no effect on cell viability in the presence of 100 μM ZnCl2 in MCF‐7 and T‐47D cells. In a wound healing assay, 100 μM ZnCl2 treatment inhibited cell migration of MCF‐7 and T‐47D cells, whereas ZnT5 knockdown promoted cell migration, decreased E‐cadherin expression and increased vimentin, slug and matrix metalloproteinase 9 expression. Antibody arrays showed that ZnT5 knockdown increased the expression of SMAD1, and that dorsomorphin treatment inhibited the promotion of migratory ability induced by ZnT5 knockdown. The results of this study revealed that both ZnT5 may be involved in less aggressive breast cancer subtypes, possibly through inhibition of cell migration. [ABSTRACT FROM AUTHOR]

Noroviruses are a prevalent cause of human viral gastroenteritis, yet the precise mechanisms underlying their infection cycle, particularly their interactions with and entry into cells, remain poorly understood. Human norovirus (HuNoV) primarily targets human small intestinal epithelial cells, within which 3- O -sulfogalactosylceramide (sulfatide) ranks among the most abundant glycosphingolipids (GSLs). While sulfatide involvement in the binding and infection mechanism of several viruses has been documented, its interaction with noroviruses remains underexplored. This study investigated whether noroviruses interact with sulfatide. We found that the recombinant viral capsid protein VP1 of HuNoV (genogroups I and II) and murine norovirus (genogroup V) exhibited robust binding to sulfatide compared with other tested GSLs using enzyme-linked immunosorbent assay, thin-layer chromatography binding assay and real-time quantitative reverse transcription polymerase chain reaction binding assay. VP1 also bound 3- O -sulfated lactosylceramide, which shares the 3- O -sulfated galactose moiety with sulfatide. However, both VP1 and its P domain, identified as the sulfatide-binding domain, exhibited limited binding to structural analogues of sulfatide and other sulfated compounds. These findings suggest a specific recognition of the 3- O -sulfated galactose moiety. Notably, we found that sulfatide is a novel binding target for norovirus particles. Overall, our findings reveal a previously unknown norovirus–sulfatide interaction, proposing sulfatide as a potential candidate for norovirus infection receptors. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hemodynamic factors play important roles in aneurysm recurrence after endovascular treatment. OBJECTIVE: Predicting the risk of recurrence by hemodynamic analysis using an untreated aneurysm model is important because such prediction is required before treatment. METHODS: We retrospectively analyzed hemodynamic factors associated with aneurysm recurrence from pretreatment models of five recurrent and five stable posterior communicating artery (Pcom) aneurysms with no significant differences in aneurysm volume, coil packing density, or sizes of the dome, neck, or Pcom. Hemodynamic factors of velocity ratio, flow rate, pressure ratio, and wall shear stress were investigated. RESULTS: Among the hemodynamic factors investigated, velocity ratio and flow rate of the Pcom showed significant differences between the recurrence group and stable group (0.630 ± 0.062 and 0.926 ± 0.051, P= 0.016; 56.4 ± 8.9 and 121.6 ± 6.7, P= 0.008, respectively). CONCLUSIONS: Our results suggest that hemodynamic factors may be associated with aneurysm recurrence among Pcom aneurysms. Velocity and flow rate in the Pcom may be a pretreatment prognostic factor for aneurysm recurrence after endovascular treatment.