Frequent amplification of <i>PTP1B</i> is associated with poor survival of gastric cancer patients

<p>The protein tyrosine phosphatase 1B (<i>PTP1B</i>), a non-transmembrane protein tyrosine phosphatase, has been implicated in gastric pathogenesis. Several lines of recent evidences have shown that <i>PTP1B</i> is highly amplified in breast and prostate cancers. The aim of this study was to investigate <i>PTP1B</i> amplification in gastric cancer and its association with poor prognosis of gastric cancer patients, and further determine the role of <i>PTP1B</i> in gastric tumorigenesis. Our data demonstrated that <i>PTP1B</i> was significantly up-regulated in gastric cancer tissues as compared with matched normal gastric tissues by using quantitative RT-PCR (qRT-PCR) assay. In addition, copy number analysis showed that <i>PTP1B</i> was amplified in 68/131 (51.9%) gastric cancer cases, whereas no amplification was found in the control subjects. Notably, <i>PTP1B</i> amplification was positively associated with its protein expression, and was significantly related to poor survival of gastric cancer patients. Knocking down <i>PTP1B</i> expression in gastric cancer cells significantly inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrested and apoptosis. Mechanically, <i>PTP1B</i> promotes gastric cancer cell proliferation, survival and invasiveness through modulating Src-related signaling pathways, such as Src/Ras/MAPK and Src/phosphatidylinositol-3-kinase (PI3K)/Akt pathways. Collectively, our data demonstrated frequent overexpression and amplification <i>PTP1B</i> in gastric cancer, and further determined the oncogenic role of <i>PTP1B</i> in gastric carcinogenesis. Importantly, <i>PTP1B</i> amplification predicts poor survival of gastric cancer patients.</p

DataSheet_1_A d-peptide-based oral nanotherapeutic modulates the PD-1/PD-L1 interaction for tumor immunotherapy.docx

BackgroundPD-1/PD-L1 immune checkpoint inhibitors are currently the most commonly utilized agents in clinical practice, which elicit an immunostimulatory response to combat malignancies. However, all these inhibitors are currently administered via injection using antibody-based therapies, while there is a growing need for oral alternatives.MethodsThis study has developed and synthesized exosome-wrapped gold–peptide nanocomplexes with low immunogenicity, which can target PD-L1 and activate antitumor immunity in vivo through oral absorption. The SuperPDL1exo was characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), Fourier transform infrared (FTIR), X-ray photoelectron spectroscopy (XPS), and gel silver staining. The transmembrane ability of SuperPDL1exo was evaluated by flow cytometry and immunofluorescence. Cell viability was determined using the Cell Counting Kit-8 (CCK-8) assay. ELISA experiments were conducted to detect serum and tissue inflammatory factors, as well as serum biochemical indicators. Tissue sections were stained with H&E for the evaluation of the safety of SuperPDL1exo. An MC38 colon cancer model was established in immunocompetent C56BL/6 mice to evaluate the effects of SuperPDL1exo on tumor growth in vivo. Immunohistochemistry (IHC) staining was performed to detect cytotoxicity factors such as perforin and granzymes.ResultsFirst, SuperPDL1 was successfully synthesized, and milk exosome membranes were encapsulated through ultrasound, repeated freeze–thaw cycles, and extrusion, resulting in the synthesis of SuperPDL1exo. Multiple characterization results confirmed the successful synthesis of SuperPDL1exo nanoparticles. Furthermore, our data demonstrated that SuperPDL1exo exhibited excellent colloidal stability and superior cell transmembrane ability. In vitro and in vivo experiments revealed that SuperPDL1exo did not cause damage to multiple systemic organs, demonstrating its good biocompatibility. Finally, in the MC38 colon cancer mouse model, it was discovered that SuperPDL1exo could inhibit the progression of colon cancer, and this tumor-suppressive effect was mediated through the activation of tumor-specific cytotoxic T lymphocyte (CTL)-related immune responses.ConclusionThis study has successfully designed and synthesized an oral nanotherapeutic, SuperPDL1exo, which demonstrates small particle size, excellent colloidal stability, transmembrane ability in tumor cells, and biocompatibility. In vivo experiments have shown that it effectively activates T-cell immunity and exerts antitumor effects.</p