Xu, Jianjun | Search NASA

DOE OSTI2021

USP18 promotes tumor metastasis in esophageal squamous cell carcinomas via deubiquitinating ZEB1

Highlights: • High USP18 expression is positively correlated with the malignant phenotype and poor survival in ESCC patients. • Knockdown of USP18 suppressed the metastasis ability of ESCC cells in vitro and in vivo. • USP18 contributes to ESCC cell metastasis by inducing ZEB1 mediated EMT process. • USP18 acts as a deubiquitinase, and stabilises ZEB1 by reducing its poly-ubiquitination. The dysregulation of deubiquitinating enzymes (DUBs), which regulate the stability of most cellular proteins, have been implicated in many human diseases, including cancers. Ubiquitin-specific protease 18 (USP18), a member of the DUBs family, functions as a potential tumour promoter in various cancers. However, the biological function and clinical significance of USP18 in esophageal squamous cell carcinomas (ESCC) are still unclear. Here, we found that ESCC tumors had higher USP18 expression compared with that of normal esophageal epithelial tissues, and high USP18 level was significantly correlated with malignant phenotype and shorter survival in patients with ESCC. In functional experiments, USP18 knockdown significantly inhibited ESCC invasion and metastasis in vitro. Consistently, a xenograft assay showed that knockdown of USP18 in ESCC cell suppressed their dissemination to lung tissue in vivo. Furthermore, we showed that USP18 promoted ESCC cell metastasis by inducing ZEB1 mediated epithelial-mesenchymal transition (EMT). Importantly, our results demonstrated that the oncogenic effect of USP18 in ESCC is partially dependent on ZEB1 enhancement. Mechanistic investigations revealed that USP18 directly bound ZEB1 and decreased its ubiquitination to enhance the protein stability of ZEB1 in ESCC cells. Overall, our data highlighted an essential role of USP18 in ESCC metastasis, suggesting that it could be a potential diagnostic and therapeutic target for ESCC.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1997

The Stability of Radiatively Cooling Jets. 2: Nonlinear Evolution

We use two-dimensional time-dependent hydrodynamical simulations to follow the growth of the Kelvin-Helmholtz (K-H) instability in cooling jets into the nonlinear regime. We focus primarily on asymmetric modes that give rise to transverse displacements of the jet beam. A variety of Mach numbers and two different cooling curves are studied. The growth rates of waves in the linear regime measured from the numerical simulations are in excellent agreement with the predictions of the linear stability analysis presented in the first paper in this series. In the nonlinear regime, the simulations show that asymmetric modes of the K-H instability can affect the structure and evolution of cooling jets in a number of ways. We find that jets in which the growth rate of the sinusoidal surface wave has a maximum at a so-called resonant frequency can be dominated by large-amplitude sinusoidal oscillations near this frequency. Eventually, growth of this wave can disrupt the jet. On the other hand, nonlinear body waves tend to produce low-amplitude wiggles in the shape of the jet but can result in strong shocks in the jet beam. In cooling jets, these shocks can produce dense knots and filaments of cooling gas within the jet. Ripples in the surface of the jet beam caused by both surface and body waves generate oblique shock "spurs" driven into the ambient gas. Our simulations show these shock "spurs" can accelerate ambient gas at large distances from the jet beam to low velocities, which represents a new mechanism by which low-velocity bipolar outflows may be driven by high-velocity jets. Rapid entrainment and acceleration of ambient gas may also occur if the jet is disrupted. For parameters typical of protostellar jets, the frequency at which K-H growth is a maximum (or highest frequency to which the entire jet can respond dynamically) will be associated with perturbations with a period of - 200 yr. Higher frequency (shorter period) perturbations excite waves associated with body modes that produce internal shocks and only small-amplitude wiggles within the jet. The fact that most observed systems show no evidence for large-amplitude sinusoidal oscillation leading to disruption is indicative that the perturbation frequencies are generally large, consistent with the suggestion that pro- tostellar jets arise from the inner regions (r less than 1 AU) of accretion disks.

Stone, James M.↗