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Ectodomain shedding of cell-surface precursor proteins by metalloproteases generates important cellular signaling molecules. Of importance for disease is the release of ligands that activate the EGFR, such as TGFα, which is mostly carried out by ADAM17 [a member of the A-disintegrin and metalloprotease (ADAM) domain family]. EGFR ligand shedding has been linked to many diseases, in particular cancer development, growth and metastasis, as well as resistance to cancer therapeutics. Excessive EGFR ligand release can outcompete therapeutic EGFR inhibition or the inhibition of other growth factor pathways by providing bypass signaling via EGFR activation. Drugging metalloproteases directly have failed clinically because it indiscriminately affected shedding of numerous substrates. It is therefore essential to identify regulators for EGFR ligand cleavage. Here, integration of a functional shRNA genomic screen, computational network analysis, and dedicated validation tests succeeded in identifying several key signaling pathways as novel regulators of TGFα shedding in cancer cells. Most notably, a cluster of genes with NFκB pathway regulatory functions was found to strongly influence TGFα release, albeit independent of their NFκB regulatory functions. Inflammatory regulators thus also govern cancer cell growth-promoting ectodomain cleavage, lending mechanistic understanding to the well-known connection between inflammation and cancer.Implications: Using genomic screens and network analysis, this study defines targets that regulate ectodomain shedding and suggests new treatment opportunities for EGFR-driven cancers. Mol Cancer Res; 16(1); 147-61. ©2017 AACR.

Background: Signal transducer and activator of transcription 3 (STAT3) is a member of the cytoplasmic inducible transcription factors and plays an important role in mediating signals from cytokines, chemokines, and growth factors. We and others have found that STAT3 directly regulates pro-fibrotic signaling in the kidney. The STAT3 protein–protein interaction plays an important role in activating its transcriptional activity. It is necessary to identify these interactions to investigate their function in kidney disease. Here, we investigated the protein–protein interaction among three species to find crucial interactions that can be targeted to alleviate kidney disease. Method: In this study, we examined common protein–protein interactions leading to the activation or downregulation of STAT3 among three different species: humans (Homo sapiens), mice (Mus musculus), and rabbits (Oryctolagus cuniculus). Further, we chose to investigate the P300 and STAT3 interaction and performed studies of the activation of STAT3 using IL-6 and inhibition of the P300 by its specific inhibitor A-485 in pericytes. Next, we performed immunoprecipitation to confirm whether A-485 inhibits the binding of P300 to STAT3. Results: Using the STRING application from ExPASy, we found that six proteins, including PIAS3, JAK1, JAK2, EGFR, SRC, and EP300, showed highly confident interactions with STAT3 in humans, mice, and rabbits. We also found that IL-6 treatment increased the acetylation of STAT3 and increased histone 3 lysine acetylation (H3K27ac). Furthermore, we found that the disruption of STAT3 and P300 interaction by the P300 inhibitor A-485 decreased STAT3 acetylation and H3K27ac. Finally, we confirmed that the P300 inhibitor A-485 inhibited the binding of STAT3 with P300, which inhibited its transcriptional activity by reducing the expression of Ccnd1 (Cyclin D1). Conclusions: Targeting the P300 protein interaction with STAT3 may alleviate STAT3-mediated fibrotic signaling in humans and other species. [ABSTRACT FROM AUTHOR]

Background: Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population.Methods: We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided.Results: We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy.Conclusions: Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical. [ABSTRACT FROM AUTHOR]

Direct‐acting antiviral therapies (DAAs) may improve kidney function and proteinuria in certain patients with hepatitis C infection (HCV) and chronic kidney disease (CKD). To improve our understanding of HCV‐mediated kidney dysfunction, we aimed to evaluate the baseline predictors of improvement in proteinuria after DAAs in a single‐arm, pilot, clinical trial of ledipasvir 90 mg/sofosbuvir 400 mg once daily for patients with HCV genotype 1 or 4 infection and proteinuric CKD (≥300 mg proteinuria per gram creatinine). Plasma biomarkers of complement system (C3 and C4) and urinary kidney injury biomarkers were measured at baseline, 8 weeks on treatment, 12 weeks following treatment, and 1 year following treatment. We then conducted a retrospective cohort study of patients at Partners Healthcare who had baseline complement component 4 (C4) measured before DAAs for HCV and evaluated the change in estimated glomerular filtration rate (eGFR) before and after therapy. Ten patients with HCV and proteinuric CKD were enrolled in the trial. The mean age was 64 years, 70% male, 70% white, and 30% black. Baseline creatinine was 1.25 mg/dL (SD 0.44), eGFR was 65 mL/min/1.73 m2 (SD 29), and proteinuria was 0.98 g/g creatinine (SD 0.7). Sustained virologic response at 12 weeks was achieved by 80% of patients. Patients with low baseline C4 had improved proteinuria, urinary neutrophil gelatinase‐associated lipocalin, and interleukin‐18 after ledipasvir and sofosbuvir treatment. The retrospective study included 50 patients with CKD and HCV. Twenty patients (40%) had low baseline C4; these patients significantly improved their eGFR (+3.4 ± 11.2 mL/min/1.73 m2) compared to those with normal baseline C4 (−4.4 ± 12.2 mL/min/1.73 m2; P = 0.028). Conclusion: Low C4 may be a marker of kidney dysfunction that improves with DAA therapy. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a general term for a diverse variety of causes affecting kidney structure and function. The term “chronic” is because the damage to the kidneys happens slowly over a long period. Damaged kidneys cannot filter extra water and wastes out of blood as compared to the healthy kidneys. The disease prognosis and control are categorized based on disease severity, which is evaluated by glomerular filtration rate (GFR) and albuminuria, and clinical diagnosis. Progression of CKD thus causes wastes to build up in the body and is associated with many severe complications, including increased incidence of cardiovascular disease, hyperlipidemia, anemia, and metabolic bone disease. Forty percent of CKD is a result of complications associated with diabetes. Patients with diabetes are suggested to intake components that have reduced amount of carbohydrates and increased amount of proteins. Patients with CKD are suggested to intake a low protein diet. Thus, there is a fine need for CKD patients to understand the food constituents and functional components. Given the intricacies of the renal diet and the difficulties faced by patients due to conflicting recommendations and complexities faced in understanding processed food labels, there is a lot of emphasis in the present world to change the focus in CKD away from what not to eat to the concept of good nutrition as positive medicine or therapy for kidney patients. Specifically, there has been a surge in consumer interest on the beneficial role of specific foods with physiologically-active food components, so-called functional foods benefitting CKD. In the past century, increased attention to lifestyle and healthy diets has led to an increase in demand for functional foods. Thus, this review will discuss the key components that have been investigated in vivo using rodent models, some clinical trials and studies for being identified as a ‘nutraceuticals’ for patients with CKD. [ABSTRACT FROM AUTHOR]