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Background: Radiotherapy (RT) can drive cancer cells to enter a state of cellular senescence in which cells can secrete senescence‐associated secretory phenotype (SASP) and produce small extracellular vesicles (sEVs) to interact with cells in the tumor microenvironment (TME). Tumor‐derived sEVs that are taken up by recipient cells contribute to cancer cell metabolic plasticity, resistance to anticancer therapy, and adaptation to the TME. However, how radiation‐induced sEVs support oral squamous cell carcinoma (OSCC) progression remains unclear. Methods: Beta‐galactosidase staining and SASP mRNA expression analysis were used to evaluate the senescence‐associated activity of OSCC cells after irradiation. Nanoparticle tracking analysis was performed to identify radiation‐induced sEVs. Liquid chromatography–tandem mass spectrometry (LC–MS) was used to explore changes in the levels of proteins in radiation‐induced sEVs. Cell Counting Kit‐8 and colony formation assays were performed to investigate the function of radiation‐induced SASP and sEVs in vitro. A xenograft tumor model was established to investigate the functions of radiation‐induced sEVs and V‐9302 in vivo as well as the underlying mechanisms. Bioinformatics analysis was performed to determine the relationship between glutamine metabolism and OSCC recurrence. Results: We determined that the radiation‐induced SASP triggered OSCC cell proliferation. Additionally, radiation‐induced sEVs exacerbated OSCC cell malignancy. LC–MS/MS and bioinformatics analyses revealed that SLC1A5, which is a cellular receptor that participates in glutamine uptake, was significantly enriched in radiation‐induced sEVs. In vitro and in vivo, inhibiting SLC1A5 could block the oncogenic effects of radiation‐induced sEVs in OSCC. Conclusion: Radiation‐induced sEVs might promote the proliferation of unirradiated cancer cells by enhancing glutamine metabolism; this might be a novel molecular mechanism underlying radiation resistance in OSCC patients. [ABSTRACT FROM AUTHOR]

Collapse of the microvascular system is a prerequisite for radiation‐induced bone loss. Since type H vessels, a specific bone vessel subtype surrounded by platelet‐derived growth factor receptor β+ (PDGFRβ+) perivascular cells (PVCs), has been recently identified to couple angiogenesis and osteogenesis, we hypothesize that type H vessel injury initiates PDGFRβ+ PVC dysfunction, which contributes to the abnormal angiogenesis and osteogenesis after irradiation. In this study, we found that radiation led to the decrease of both type H endothelial cell (EC) and PDGFRβ+ PVC numbers. Remarkably, results from lineage tracing showed that PDGFRβ+ PVCs detached from microvessels and converted the lineage commitment from osteoblasts to adipocytes, leading to vascular injury and bone loss after irradiation. These phenotype transitions above were further verified to be associated with the decrease in hypoxia‐inducible factor‐1α (HIF‐1α)/PDGF‐BB/PDGFRβ signalling between type H ECs and PDGFRβ+ PVCs. Pharmacological blockade of HIF‐1α/PDGF‐BB/PDGFRβ signalling induced a phenotype similar to radiation‐induced bone damage, while the rescue of this signalling significantly alleviated radiation‐induced bone injury. Our findings show that the decrease in HIF‐1α/PDGF‐BB/PDGFRβ signalling between type H ECs and PDGFRβ+ PVCs after irradiation affects the homeostasis of EC‐PVC coupling and plays a part in vascular damage and bone loss, which has broad implications for effective translational therapies. [ABSTRACT FROM AUTHOR]

Elucidation of the mechanisms of T-cell-mediated antitumor responses will provide information for the rational design and development of cancer immunotherapies. Here, we found that calnexin, an endoplasmic reticulum (ER) chaperone protein, is significantly upregulated in oral squamous cell carcinoma (OSCC). Upregulation of its membranous expression on OSCC cells is associated with inhibited T-cell infiltration in tumor tissues and correlates with poor survival of patients with OSCC. We found that calnexin inhibits the proliferation of CD4 + and CD8 + T cells isolated from the whole blood of healthy donors and patients with OSCC and inhibits the secretion of IFNγ, TNFα, and IL2 from these cells. Furthermore, in a melanoma model, knockdown of calnexin enhanced the infiltration and effector functions of T cells in the tumor microenvironment and conferred better control of tumor growth, whereas treatment with a recombinant calnexin protein impaired the infiltration and effector functions of T cells and promoted tumor growth. We also found that calnexin enhanced the expression of PD-1 on CD4 + and CD8 + T cells by restraining the DNA methylation status of a CpG island in the PD-1 promoter. Thus, this work uncovers a mechanism by which T-cell antitumor responses are regulated by calnexin in tumor cells and suggests that calnexin might serve as a potential target for the improvement of antitumor immunotherapy., (©2018 American Association for Cancer Research.)

Oral squamous cell carcinoma (OSCC) is a common and aggressively malignant tumor of the head and neck region. Long non-coding RNAs (lncRNAs) are important regulatory molecules in many types of cancer. However, there are limited studies on the role of lncRNAs in OSCC. In this study, we identified that lncRNA P4713 was one of the most up-regulated lncRNAs in OSCC by exploring the expression profile of lncRNAs/mRNAs in four pairs of OSCC samples and adjacent non-cancer tissues. In addition, silencing of P4713 inhibited OSCC proliferation, migration, and invasion in vitro . Furthermore, through bioinformatics analysis and functional experiments, we found that decreased P4713 expression affected the expression and phosphorylation of Janus Kinase (JAK) 2 and signal transducer and activator of transcription (STAT) 3. Taken together, the results suggest that P4713 contributes to OSCC cell proliferation, migration, and invasion by activating the JAK/STAT3 pathway. Accordingly, this molecule could be a potential biomarker and therapeutic target in the treatment of OSCC., Competing Interests: None., (IJCEP Copyright © 2017.)

Dysregulation of miRNAs has been shown to contribute to the carcinogenesis and progression of nasopharyngeal carcinoma (NPC). Our previous microarray data showed that miR-16 expression is significantly decreased in archived NPC tissues. Here, we confirmed that miR-16 was reduced in NPC cell lines and freshly-frozen samples. Ectopic expression of miR-16 suppressed NPC cell proliferation, migration, and invasion in vitro and inhibited tumor growth and metastatic colonization in the lung in vivo. Furthermore, fibroblast growth factor 2 (FGF2) was identified as a direct target of miR-16, and both phosphoinositide-3- kinase/AKT (PI3K/AKT) and mitogen-activated protein kinase (MAPK) signaling pathways were repressed after miR-16 overexpression. In addition, the restoration of FGF2 reversed the suppressive effects of miR-16. Together, these results indicated that miR-16 suppresses NPC carcinogenesis and progression by targeting FGF2, thereby representing a potential target for miRNA-based therapy for NPC in the future.

Background: The purpose of this study was to synthesize and evaluate hyperbranched cationic glycogen derivatives as an efficient nonviral gene-delivery vector., Methods: A series of hyperbranched cationic glycogen derivatives conjugated with 3-(dimethylamino)-1-propylamine (DMAPA-Glyp) and 1-(2-aminoethyl) piperazine (AEPZ-Glyp) residues were synthesized and characterized by Fourier-transform infrared and hydrogen-1 nuclear magnetic resonance spectroscopy. Their buffer capacity was assessed by acid-base titration in aqueous NaCl solution. Plasmid deoxyribonucleic acid (pDNA) condensation ability and protection against DNase I degradation of the glycogen derivatives were assessed using agarose gel electrophoresis. The zeta potentials and particle sizes of the glycogen derivative/pDNA complexes were measured, and the images of the complexes were observed using atomic force microscopy. Blood compatibility and cytotoxicity were evaluated by hemolysis assay and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, respectively. pDNA transfection efficiency mediated by the cationic glycogen derivatives was evaluated by flow cytometry and fluorescence microscopy in the 293T (human embryonic kidney) and the CNE2 (human nasopharyngeal carcinoma) cell lines. In vivo delivery of pDNA in model animals (Sprague Dawley rats) was evaluated to identify the safety and transfection efficiency., Results: The hyperbranched cationic glycogen derivatives conjugated with DMAPA and AEPZ residues were synthesized. They exhibited better blood compatibility and lower cytotoxicity when compared to branched polyethyleneimine (bPEI). They were able to bind and condense pDNA to form the complexes of 100-250 nm in size. The transfection efficiency of the DMAPA-Glyp/pDNA complexes was higher than those of the AEPZ-Glyp/pDNA complexes in both the 293T and CNE2 cells, and almost equal to those of bPEI. Furthermore, pDNA could be more safely delivered to the blood vessels in brain tissue of Sprague Dawley rats by the DMAPA-Glyp derivatives, and then expressed as green fluorescence protein, compared with the control group., Conclusion: The hyperbranched cationic glycogen derivatives, especially the DMAPA-Glyp derivatives, showed high gene-transfection efficiency, good blood compatibility, and low cyto toxicity when transfected in vitro and in vivo, which are novel potential nonviral gene vectors.

Gene therapy has been considered as a promising method for treatment of many diseases, such as acquired and genetic diseases. At present, there are two major vehicles for gene delivery including viral vectors and nonviral vectors. Viral vectors appear as high gene transfection efficiency, but some deficiencies such as inflammatory responses, recombination and mutagenesis have limited their use. On account of low pathogenicity, safety and cost-effectiveness, nonviral vectors have been attracted much attention. Cationic polymers are one of the nonviral vectors which have been widely studied. This review focuses on the structure of the cationic polymers and the interaction mechanism between the vector and DNA. We try to provide a framework for the future design and synthesis of nonviral vectors with high transfection efficiency and low toxicity for gene therapy.