Background Forkhead box M1 (FOXM1) is a proliferation-associated transcription factor of the forkhead box proteins superfamily, which includes four isoforms FOXM1a, b, c, and d. FOXM1 has been implicated in hepatocellular carcinoma (HCC) progression, but the underlying molecular mechanism remains elusive. In this study, we aim to clarify the molecular basis for FOXM1-mediated HCC progression. Methods Bioinformatic analysis was used to explore the differentially expressed genes predicting HCC proliferation. The expression of FOXM1 and kinesin family member (KIF)4A was confirmed by western blotting and immunohistochemistry in HCC tissues. Kaplan-Meier survival analysis was conducted to analyze the clinical impact of FOXM1 and KIF4A on HCC. The effect of FOXM1 on the regulation of KIF4A expression was studied in cell biology experiments. The interaction between KIF4A and FOXM1 was analyzed by chromatin immunoprecipitation and luciferase experiments. A series of experiments was performed to explore the functions of FOXM1/KIF4A in HCC progression, such as cell proliferation, cell growth, cell viability, and cell cycle. A xenograft mouse model was used to explore the regulatory effect of FOXM1-KIF4A axis on HCC tumor growth. Results FOXM1 and KIF4A were overexpressed in human primary HCC tissues compared to that in matched adjacent normal liver tissue and are significant risk factors for HCC recurrence and shorter survival. We found that KIF4A was dominantly regulated by FOXM1c among the four isoforms, and further identified KIF4A as a direct downstream target of FOXM1c. Inhibiting FOXM1 decreased KIF4A expression in HCC cells, whereas its overexpression had the opposite effect. FOXM1-induced HCC cell proliferation was dependent on elevated KIF4A expression as KIF4A knockdown abolished FOXM1-induced proliferation of HCC cells both in vitro and in vivo. Conclusion The FOXM1–KIF4A axis mediates human HCC progression and is a potential therapeutic target for HCC treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1202-3) contains supplementary material, which is available to authorized users.

It is of both fundamental and practical interest to study the flow physics in the manipulation of droplets. In this paper, we investigate complex flow in liquid droplets actuated by a linear gradient of wettability using dissipative particle dynamics simulation. The wetting property of the substrate ranging from hydrophilic to hydrophobic is achieved by adjusting the conservative solid-liquid interactions which results in a variation of solid-liquid surface tension. The internal three-dimensional velocity field with transverse flow in droplet is revealed and analyzed in detail. When the substrate is hydrophobic, it is found that there is slight deformation but strong flow circulation inside the droplet, and the droplet rolling is the dominant mechanism for the movement. However, large deformation of the droplet is generated after the droplet reaches the hydrophilic surface, and a mechanism combining rolling and sliding dominates the transportation of the droplet. Another interesting finding is that the thermal fluctuation can accelerate the spontaneous motion of a liquid droplet under a wetting gradient. The effects of the steepness of wetting gradient and the size of droplet on the translation speed are studied as well.

Cancer develops and progresses often by inactivating p53. Here, we unveil nerve growth factor receptor (NGFR, p75NTR or CD271) as a novel p53 inactivator. p53 activates NGFR transcription, whereas NGFR inactivates p53 by promoting its MDM2-mediated ubiquitin-dependent proteolysis and by directly binding to its central DNA binding domain and preventing its DNA-binding activity. Inversely, NGFR ablation activates p53, consequently inducing apoptosis, attenuating survival, and reducing clonogenic capability of cancer cells, as well as sensitizing human cancer cells to chemotherapeutic agents that induce p53 and suppressing mouse xenograft tumor growth. NGFR is highly expressed in human glioblastomas, and its gene is often amplified in breast cancers with wild type p53. Altogether, our results demonstrate that cancers hijack NGFR as an oncogenic inhibitor of p53.DOI: http://dx.doi.org/10.7554/eLife.15099.001

Molecular dynamics simulation is utilized to investigate the ionic transport of NaCl in solution through a graphene nanopore under an applied electric field. Results show the formation of concentration polarization layers in the vicinity of the graphene sheet. The nonuniformity of the ion distribution gives rise to an electric pressure which drives vortical motions in the fluid if the electric field is sufficiently strong to overcome the influence of viscosity and thermal fluctuations. The relative importance of hydrodynamic transport and thermal fluctuations in determining the pore conductivity is investigated. A second important effect that is observed is the mass transport of water through the nanopore, with an average velocity proportional to the applied voltage and independent of the pore diameter. The flux arises as a consequence of the asymmetry in the ion distribution which can be attributed to differing mobilities of the sodium and chlorine ions, and, to the polarity of water molecules. The accumulation of liquid molecules in the vicinity of the nanopore due to reorientation of the water dipoles by the local electric field is seen to result in a local increase in the liquid density. Results confirm that the electric conductance is proportional to the nanopore diameter for the parameter regimes that we simulated. The occurrence of fluid vortices is found to result in an increase in the effective electrical conductance.