The disulfide catalyst QSOX1 maintains the colon mucosal barrier by regulating Golgi glycosyltransferases.

Mucus is made of enormous mucin glycoproteins that polymerize by disulfide crosslinking in the Golgi apparatus. QSOX1 is a catalyst of disulfide bond formation localized to the Golgi. Both QSOX1 and mucins are highly expressed in goblet cells of mucosal tissues, leading to the hypothesis that QSOX1 catalyzes disulfide-mediated mucin polymerization. We found that knockout mice lacking QSOX1 had impaired mucus barrier function due to production of defective mucus. However, an investigation on the molecular level revealed normal disulfide-mediated polymerization of mucins and related glycoproteins. Instead, we detected a drastic decrease in sialic acid in the gut mucus glycome of the QSOX1 knockout mice, leading to the discovery that QSOX1 forms regulatory disulfides in Golgi glycosyltransferases. Sialylation defects in the colon are known to cause colitis in humans. Here we show that QSOX1 redox control of sialylation is essential for maintaining mucosal function.

Correction: Inhibition of fibroblast secreted QSOX1 perturbs extracellular matrix in the tumor microenvironment and decreases tumor growth and metastasis in murine cancer models.

[This corrects the article DOI: 10.18632/oncotarget.27438.].

Inhibition of fibroblast secreted QSOX1 perturbs extracellular matrix in the tumor microenvironment and decreases tumor growth and metastasis in murine cancer models.

Extracellular matrix (ECM) plays an important role in tumor development and dissemination, but few points of therapeutic intervention targeting ECM of the tumor microenvironment have been exploited to date. Recent observations suggest that the enzymatic introduction of disulfide bond cross-links into the ECM may be modulated to affect cancer progression. Specifically, the disulfide bond-forming activity of the enzyme Quiescin sulfhydryl oxidase 1 (QSOX1) is required by fibroblasts to assemble ECM components for adhesion and migration of cancer cells. Based on this finding and the increased QSOX1 expression in the stroma of aggressive breast carcinomas, we developed monoclonal antibody inhibitors with the aim of preventing QSOX1 from participating in pro-metastatic ECM remodeling. Here we show that QSOX1 inhibitory antibodies decreased tumor growth and metastasis in murine cancer models and had added benefits when provided together with chemotherapy. Mechanistically, the inhibitors dampened stromal participation in tumor development, as the tumors of treated animals showed fewer myofibroblasts and poorer ECM organization. Thus, our findings demonstrate that specifically targeting excess stromal QSOX1 secreted in response to tumor-cell signaling provides a means to modulate the tumor microenvironment and may complement other therapeutic approaches in cancer.

Sensing of Vimentin mRNA in 2D and 3D Models of Wounded Skin Using DNA-Coated Gold Nanoparticles.

Wound healing is a highly complex biological process, which is accompanied by changes in cell phenotype, variations in protein expression, and the production of active biomolecules. Currently, the detection of proteins in cells is done by immunostaining where the proteins in fixed cells are detected by labeled antibodies. However, immunostaining cannot provide information about dynamic processes in living cells, within the whole tissue. Here, an easy method is presented to detect the transition of epithelial to mesenchymal cells during wound healing. The method employs DNA-coated gold nanoparticle fluorescent nanoprobes to sense the production of Vimentin mRNA expressed in mesenchymal cells. Fluorescence microscopy is used to achieve temporal detection of Vimentin mRNA in wounds. 3D light-sheet microscopy is utilized to observe the dynamic expression of Vimentin mRNA spatially around the wounded site in skin tissue. The use of DNA-gold nanoprobes to detect mRNA expression during wound healing opens up new possibilities for the study of real-time mechanisms in complex biological processes.

Graphene Oxide-Upconversion Nanoparticle Based Optical Sensors for Targeted Detection of mRNA Biomarkers Present in Alzheimer's Disease and Prostate Cancer.

The development of new sensors for the accurate detection of biomarkers in biological fluids is of utmost importance for the early diagnosis of diseases. Next to advanced laboratory techniques, there is a need for relatively simple methods which can significantly broaden the availability of diagnostic capability. Here, we demonstrate the successful application of a sensor platform based on graphene oxide and upconversion nanoparticles (NPs) for the specific detection of mRNA-related oligonucleotide markers in complex biological fluids. The combination of near-infrared light upconversion with low-background photon counting readout enables reliable detection of low quantities of small oligonucleotide sequences in the femtomolar range. We demonstrate the successful detection of analytes relevant to mRNAs present in Alzheimer's disease as well as prostate cancer in human blood serum. The high performance and relative simplicity of the upconversion NP-graphene sensor platform enables new opportunities in early diagnosis based on specific detection of oligonucleotide sequences in complex environments.