Ubiquitin specific protease 4 (USP4) is a member of the USPs family, which catalyzes the cleavage of ubiquitin from a series of protein substrates, thereby modulating a number of cellular signaling pathways. In this study, we aimed to explore the expression profile of USP4 in lung adenocarcinoma (LUAD) using large patient cohorts in the Cancer Genome Atlas and the International Cancer Genome Consortium and to investigate its prognostic value and the possible mechanisms of its dysregulation. Results showed that USP4 was significantly downregulated in LUAD tissues (N = 514) compared with the normal controls (N = 59). The high USP4 expression group had significantly better overall survival (OS) and recurrence-free survival (RFS). Multivariate analysis showed that preserved USP4 expression was an independent prognostic factor of favorable OS (HR: 0.574, 95%CI: 0.427-0.771, P < 0.001) and RFS (HR: 0.625, 95%CI: 0.444-0.880, P = 0.007) in LUAD. In comparison, although USP4 was downregulated in lung squamous cell carcinoma, its expression had no prognostic value in term of OS and RFS. By examining USP4 DNA copy number alterations (CNAs) (N = 511) and DNA methylation (N = 453) in LUAD, we found that DNA shallow deletion was frequent (-1, N = 239, 46.8%) and was associated with significantly decreased USP4 expression compared with the copy-neutral (0) cases. The methylation status of some CpG sites in USP4 DNA was negatively correlated with USP4 expression. Based on these findings, we infer that USP4 expression might be a favorable biomarker in terms of OS and RFS in LUAD patients. DNA shallow deletion and hypermethylation might be two important mechanisms of decreased USP4 in these patients. © 2018 IUBMB Life, 70(7):670-677, 2018.
Resistin, secreted by macrophages in tumor microenvironment, has never been investigated in pancreatic cancer models, despite a vibrant tumor microenvironment around pancreatic tumors. We evaluated serum resistin levels in healthy individuals versus pancreatic cancer patients representing different tumor grades. In vitro mechanistic analysis involved MiaPaCa‐2 and SW1990 cells. Resistin signaling depends on binding of resistin to its cognitive receptors. Therefore, we silenced adenylyl cyclase‐associated protein 1 (CAP1) and toll‐like receptor 4 (TLR4), its two known receptors, individually as well as in combination, by short hairpin RNA (shRNA). Effect of resistin on cell proliferation, migration, invasion, cell cycle, and sensitivity to gemcitabine was studied without or with silencing of resistin receptors CAP1 and/or TLR4. The results were also confirmed in vivo in mice xenografted with MiaPaCa‐2 cells without or with receptor silencing. We report high resistin levels in pancreatic cancer patients which correlate positively with tumor grades. We observed a marked reduction in the resistin‐induced proliferation, migration, invasion, and cell cycle of pancreatic cancer cells MiaPaCa‐2 and SW1990 when the receptors were silenced. The results were confirmed in vivo wherein resistin effects were significantly attenuated in MiaPaCa‐2 xenografts with silenced receptors. The combined silencing of CAP1 and TLR4 was found to be most effective in vitro and in vivo. We found activation of STAT3 by resistin in vivo and in vitro which was dependent on the presence of CAP1 and TLR4. Further, resistin was found to induce resistance to gemcitabine through its receptors. Our results describe novel functional roles of resistin with implications toward a better understanding of pancreatic tumor microenvironment.
Despite that nickel−iron spinel (NiFe 2 O 4 ) exhibits excellent oxygen evolution catalytic activity, its unsatisfactory mass transport limits further improvement in catalytic performance. Herein, we report an electrode with three-dimensional ordered macroporous NiFe 2 O 4 on carbon cloth (3DOM-NiFe 2 O 4 /CC) for oxygen evolution reaction (OER). The ordered macropores endow the electrode with high porosity and short diffusion passages, which facilitate fast electrolyte flow and gas spillage, thereby enhancing the mass transport capability. Meanwhile, the highly conductive carbon cloth substrate enables the electrons to transfer rapidly through the electrode. Benefited from the excellent mass transport and electron mobility, the asprepared electrode exhibited high catalytic activity with a small overpotential of 238 mV for a driving current density of 10 mA cm −2 and a small Tafel slope of 57.2 mV dec −1 for OER.
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