Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>We had previously demonstrated overexpression of fibroblast growth factor receptor-4 (FGFR4) in hepatocellular carcinoma (HCC). However, additional molecular mechanisms resulting in amplified FGFR4 signaling in HCC remain under-studied. Here, we studied the mechanistic role of its co-receptor klotho-beta (KLB) in driving elevated FGFR4 activity in HCC progression.</p> <p>Results</p> <p>Quantitative real-time PCR analysis identified frequent elevation of KLB gene expression in HCC tumors relative to matched non-tumor tissue, with a more than two-fold increase correlating with development of multiple tumors in patients. KLB-silencing in Huh7 cells decreased cell proliferation and suppressed FGFR4 downstream signaling. While transient repression of KLB-FGFR4 signaling decreased protein expression of alpha-fetoprotein (AFP), a HCC diagnostic marker, prolonged inhibition enriched for resistant HCC cells exhibiting increased liver stemness.</p> <p>Conclusions</p> <p>Elevated KLB expression in HCC tissues provides further credence to the oncogenic role of increased FGFR4 signaling in HCC progression and represents a novel biomarker to identify additional patients amenable to anti-FGFR4 therapy. The restricted tissue expression profile of KLB, together with the anti-proliferative effect observed with KLB-silencing, also qualifies it as a specific and potent therapeutic target for HCC patients. The enrichment of a liver stem cell-like population in response to extended KLB-FGFR4 repression necessitates further investigation to target the development of drug resistance.</p

Role of interpersonal trust in knowledge sharing.

The objective of our study is to address the importance of interpersonal trust on knowledge sharing. Few studies have investigated the impact of interpersonal trust on knowledge sharing between individuals within an organization. In particular, little research has been done to examine the effects of trust on specifically knowledge giving and knowledge seeking behaviours. Thus, our research aims to fill up these gaps by studying the effects of two types of trust, namely affect-based trust and cognition-based trust, on the level of nowledge giving and knowledge seeking behaviours exhibited between pairs of individuals within an organization

Dual-Responsive Carbon Dots for Tumor Extracellular Microenvironment Triggered Targeting and Enhanced Anticancer Drug Delivery

In this work, pH/redox dual-responsive carbon dots (CDs-RGD-Pt­(IV)-PEG) were fabricated for tumor extracellular microenvironment triggered targeting and enhanced anticancer drug delivery. The system consists of fluorescent carbon dots as imaging-guided drug nanocarriers, cisplatin­(IV) as prodrug, and RGD peptide as active targeting ligand, which is covered by monomethoxypolyethylene glycol (mPEG) through tumor extracellular pH (6.5–6.8) responsive benzoic-imine bond. The drug nanocarriers could be tracked by multicolor fluorescence of carbon dots. After the hydrolysis of benzoic-imine bond at the tumor extracellular pH to expose the inner targeting RGD peptide, the drug nanocarriers showed effective uptake by cancer cells through RGD-integrin α_<i>v</i>β₃ (ligand–receptor) interaction. Upon the internalization, the loaded cisplatin­(IV) prodrug was reduced to cytotoxic cisplatin in reductive cytosol of cancer cells to exhibit therapeutic effects. Confocal imaging, flow cytometry, and cell viability assays using CDs-RGD-Pt­(IV)-PEG were performed to reveal the enhanced uptake and better therapeutic efficiency to cancer cells with high integrin α_<i>v</i>β₃ expression at tumor extracellular pH than that in physiological condition. The developed CDs-RGD-Pt­(IV)-PEG offers a new strategy to provide safe and effective therapeutic agents based on carbon dots for promising cancer therapy

Fumarate Hydratase-deficient Cell Line NCCFH1 as a New In Vitro Model of Hereditary Papillary Renal Cell Carcinoma Type 2

International audienceBackground/Aim: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant disorder characterized by fumarate hydratase (FH) gene mutation. It is associated with the development of very aggressive kidney tumors, characterized by early onset and high metastatic potential, and has no effective therapy. The aim of the study was to establish a new preclinical platform for investigating morphogenetic and metabolic features, and alternative therapy of metastatic hereditary papillary renal cell carcinoma type 2 (PRCC2).Materials and Methods: Fresh cells were collected from pleural fluid of a patient with metastatic hereditary PRCC2. Morphogenetic and functional characteristics were evaluated via microscopy, FH gene sequencing analysis, real-time polymerase chaine reaction and enzymatic activity measurement. We performed bioenergetic analysis, gene-expression profiling, and cell viability assay with 19 anti-neoplastic drugs.Results: We established a new in vitro model of hereditary PRCC2 – the NCCFH1 cell line. The cell line possesses a c.1162 delA – p.Thr375fs frameshift mutation in the FH gene. Our findings indicate severe attenuation of oxidative phosphorylation and glucose-dependent growth of NCCFH1 cells that is consistent with the Warburg effect. Furthermore, gene-expression profiling identified that the most prominent molecular features reflected a high level of apoptosis, cell adhesion, and cell signaling. Drug screening revealed a marked sensitivity of FH −/− cells to mitoxantrone, epirubicin, topotecan and a high sensitivity to bortezomib.Conclusion: We demonstrated that the NCCFH1 cell line is a very interesting preclinical model for studying the metabolic features and testing new therapies for hereditary PRCC2, while bortezomib may be a potential efficient therapeutic option

A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics

10.1002/advs.202001374ADVANCED SCIENCE71