Ablation of the GDP-fucose transporter suppresses lung cancer cell proliferation and migration by reducing expression of PD-L1.

Fucosylation, an important post-translational modification, is closely related to the development of tumors. In the microenvironment of lung cancer, expression of PD-L1 and fucosylation is abnormally upregulated. However, the correlation between PD-L1 expression and its fucosylation in lung adenocarcinoma (LUAD) remains unclear. The GDP-fucose transporter (GFT) is a key molecule in cellular fucosylation. To explore the correlation between fucosylation and PD-L1 expression, we knocked out the GFT-encoding gene SLC35C1 in mouse Lewis lung adenocarcinoma cells and in human H1299 lung adenocarcinoma cells. Loss of SLC35C1 impaired the phosphorylation of EGFR and its downstream target ERK. Moreover, loss of SLC35C1 up-regulated the expression of ß-TrCP, a PD-L1 E3 ligase, thereby promoting the ubiquitination of PD-L1 and its subsequent degradation. The down-regulated expression of PD-L1 leads to a decline in lung cancer cell proliferation and migration. These results suggest that fucosylation partially influences LUAD tumorigenesis by regulating PD-L1 expression.

Core fucosylation and its roles in gastrointestinal glycoimmunology.

Glycosylation is a common post-translational modification in eukaryotic cells. It is involved in the production of many biologically active glycoproteins and the regulation of protein structure and function. Core fucosylation plays a vital role in the immune response. Most immune system molecules are core fucosylated glycoproteins such as complements, cluster differentiation antigens, immunoglobulins, cytokines, major histocompatibility complex molecules, adhesion molecules, and immune molecule synthesis-related transcription factors. These core fucosylated glycoproteins play important roles in antigen recognition and clearance, cell adhesion, lymphocyte activation, apoptosis, signal transduction, and endocytosis. Core fucosylation is dominated by fucosyltransferase 8 (Fut8), which catalyzes the addition of α-1,6-fucose to the innermost GlcNAc residue of N-glycans. Fut8 is involved in humoral, cellular, and mucosal immunity. Tumor immunology is associated with aberrant core fucosylation. Here, we summarize the roles and potential modulatory mechanisms of Fut8 in various immune processes of the gastrointestinal system.

Expression of GnT-III decreases chemoresistance via negatively regulating P-glycoprotein expression: Involvement of the TNFR2-NF-κB signaling pathway.

The phenomenon of multidrug resistance (MDR) is called chemoresistance with respect to the treatment of cancer, and it continues to be a major challenge. The role of N-glycosylation in chemoresistance, however, remains poorly understood. Here, we established a traditional model for adriamycin resistance in K562 cells, which are also known as K562/adriamycin-resistant (ADR) cells. Lectin blot, mass spectrometry, and RT-PCR analysis showed that the expression levels of N-acetylglucosaminyltransferase III (GnT-III) mRNA and its products, bisected N-glycans, are significantly decreased in K562/ADR cells, compared with the levels in parent K562 cells. By contrast, the expression levels of both P-glycoprotein (P-gp) and its intracellular key regulator, NF-κB signaling, are significantly increased in K562/ADR cells. These upregulations were sufficiently suppressed by the overexpression of GnT-III in K562/ADR cells. We found that the expression of GnT-III consistently decreased chemoresistance for doxorubicin and dasatinib, as well as activation of the NF-κB pathway by tumor necrosis factor (TNF) α, which binds to two structurally distinct glycoproteins, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2), on the cell surface. Interestingly, our immunoprecipitation analysis revealed that only TNFR2, but not TNFR1, contains bisected N-glycans. The lack of GnT-III strongly induced TNFR2's autotrimerization without ligand stimulation, which was rescued by the overexpression of GnT-III in K562/ADR cells. Furthermore, the deficiency of TNFR2 suppressed P-gp expression while it increased GnT-III expression. Taken together, these results clearly show that GnT-III negatively regulates chemoresistance via the suppression of P-gp expression, which is regulated by the TNFR2-NF/κB signaling pathway.

Engineering white blood cell membrane-camouflaged nanocarriers for inflammation-related therapeutics.

White blood cells (WBCs) play essential roles against inflammatory disorders, bacterial infections, and cancers. Inspired by nature, WBC membrane-camouflaged nanocarriers (WBC-NCs) have been developed to mimic the "dynamic" functions of WBCs, such as transendothelial migration, adhesion to injured blood vessels, etc, which make them promising for diverse medical applications. WBC-NCs inherit the cell membrane antigens of WBCs, while still exhibiting the robust inflammation-related therapeutic potential of synthetic nanocarriers with excellent (bio)physicochemical performance. This review summarizes the proposed concept of cell membrane engineering, which utilizes physical engineering, chemical modification, and biological functionalization technologies to endow the natural cell membrane with abundant functionalities. In addition, it highlights the recent progress and applications of WBC-NCs for inflammation targeting, biological neutralization, and immune modulation. Finally, the challenges and opportunities in realizing the full potential of WBC-NCs for the manipulation of inflammation-related therapeutics are discussed.

Cell membrane-camouflaged inorganic nanoparticles for cancer therapy.

Inorganic nanoparticles (INPs) have been paid great attention in the field of oncology in recent past years since they have enormous potential in drug delivery, gene delivery, photodynamic therapy (PDT), photothermal therapy (PTT), bio-imaging, driven motion, etc. To overcome the innate limitations of the conventional INPs, such as fast elimination by the immune system, low accumulation in tumor sites, and severe toxicity to the organism, great efforts have recently been made to modify naked INPs, facilitating their clinical application. Taking inspiration from nature, considerable researchers have exploited cell membrane-camouflaged INPs (CMCINPs) by coating various cell membranes onto INPs. CMCINPs naturally inherit the surface adhesive molecules, receptors, and functional proteins from the original cell membrane, making them versatile as the natural cells. In order to give a timely and representative review on this rapidly developing research subject, we highlighted recent advances in CMCINPs with superior unique merits of various INPs and natural cell membranes for cancer therapy applications. The opportunity and obstacles of CMCINPs for clinical translation were also discussed. The review is expected to assist researchers in better eliciting the effect of CMCINPs for the management of tumors and may catalyze breakthroughs in this area.

α1,6-Fucosyltransferase contributes to cell migration and proliferation as well as to cancer stemness features in pancreatic carcinoma.

BACKGROUND: Pancreatic carcinoma is one of the deadliest malignant diseases, in which the increased expression of α1,6-fucosyltransferase (FUT8), a sole enzyme responsible for catalyzing core fucosylation, has been reported. However, its pathological roles and regulatory mechanisms remain largely unknown. Here, we use two pancreatic adenocarcinoma cell lines, MIA PaCa-2 and PANC-1 cells, as cell models, to explore the relationship of FUT8 with the malignant transformation of PDAC. METHODS: FUT8 knockout (FUT8-KO) cells were established by the CRISPR/Cas9 system. Cell migration was analyzed by transwell and wound-healing assays. Cell proliferation was examined by MTT and colony-formation assays. Cancer stemness markers and spheroid formations were used to analyzed cancer stemness features. RESULTS: Deficiency of FUT8 inhibited cell migration and proliferation in both MIA PaCa-2 and PANC-1 cells compared with wild-type cells. Moreover, the expression levels of cancer stemness markers such as EpCAM, CXCR4, c-Met, and CD133 were decreased in the FUT8-KO cells compared with wild-type cells. Also, the spheroid formations in the KO cells were loose and unstable, which could be reversed by restoration with FUT8 gene in the KO cells. Additionally, FUT8-KO increased the chemosensitivity to gemcitabine, which is the first-line therapy for advanced pancreatic cancer. CONCLUSIONS: FUT8-KO reduced the cell proliferation and migration. Our results are the first to suggest that the expression of FUT8 is involved in regulating the stemness features of pancreatic cancer cells. GENERAL SIGNIFICANCE: FUT8 could provide novel insights for the treatment of pancreatic carcinoma.

Core fucosylation of copper transporter 1 plays a crucial role in cisplatin-resistance of epithelial ovarian cancer by regulating drug uptake.

Core fucosylation catalyzed by core fucosyltransferase (Fut8) contributes to the progressions of epithelial ovarian cancer (EOC). Copper transporter 1 (CTR1), which contains one N-glycan on Asn15 , mediates cellular transport of cisplatin (cDDP), and plays an important role in the process of cDDP-resistance in EOC. In the present study, we found that the core fucosylation level elevated significantly in the sera of cDDP-treated EOC patients. The in vitro assays also indicate that core fucosylation of CTR1 was significantly upregulated in cDDP-resistant A2780CP cells compared to the cDDP-sensitive A2780S cells. Intriguingly, the hyper core fucosylation suppressed the CTR1-cDDP interactions and cDDP-uptake into A2780CP cells. Conversely, contrast to the Fut8+/+ mouse ovarian epithelial cells, the Fut8-deleted (Fut8-/- ) cells obviously showed higher cDDP-uptake. Furthermore, the recovered core fucosylation induced the suppression of cDDP-uptake in Fut8-restored ovarian epithelial cells. In addition, the core fucosylation could regulate the phosphorylation of cDDP-resistance-associated molecules, such as AKT, ERK, JNK, and mTOR. Our findings suggest that the core fucosylation of CTR1 plays an important role in the cellular cDDP-uptake and thus provide new strategies for improving the outcome of cDDP based chemotherapy of EOC.

Association of TP53 codon 72 genotype polymorphism and environmental factors with esophageal squamous cell carcinoma in the Mongolian population of the Chinese region of Inner Mongolia.

The present study analyzed the association of tumor protein p53 (TP53) Pro72Arg polymorphism with esophageal squamous cell carcinoma (ESCC) in the Mongolian population of Tongliao (Inner Mongolia, China). Restriction fragment length polymorphism-polymerase chain reaction was used to detect the genotype distribution of TP53 Pro72Arg polymorphism in 100 patients with ESCC and 50 healthy controls from the same population. Besides, the correlation between ESCC in Mongolian patients and various factors such as age, sex, cigarette smoking and alcohol consumption was analyzed. χ2 test revealed significant associations between alcohol consumption (P=0.00006) and cigarette smoking (P=0.00076) and ESCC in Mongolian patients. Notably, the Pro72 allele was significantly enriched in patients with ESCC compared with its abundance in the healthy control group, and the genotype of Pro/Arg on p53 codon 72 was confirmed to exhibit a significant correlation with ESCC in Mongolian patients. The present study demonstrated that alcohol drinking and cigarette smoking were risk factors for ESCC in the Mongolian population. Mongolian patients who carry the partocular genotype of Arg/Pro or Pro/Pro on p53 codon 72 may be more likely to develop ESCC. Compared with the p53 codon 72 genotype Arg/Arg, the TP53 Pro72 allele increased the risk of ESCC in Mongolian patients by 1.659-fold.

Spontaneous epidural hematoma complicated by systemic lupus erythematosus: one case report.

In this study, an unusual case of intracranial hemorrhage is presented. It is spontaneous epidural hemorrhage, the complication of Systemic Lupus Erythematosus. In this case, a 29-year-old female presented with vomiting and continuous headache and computed tomography revealed the right frontal parietal and temporal epidural hematoma. The patient had been diagnosed SLE one year ago. Together, these observations indicated that the patient needs a surgery to reduce the intracranial pressure. Following surgery, the symptoms were eradicated but 7 hours later after surgery the review head CT showed that left epidural hemorrhage. According to the surgery index, we decided to give the patient non-operative treatment and the intracranial hemorrhage was under control. We thought this was the surgery complication but it's not. On the eighth day after surgery, the patient had a sudden headache with vomiting again and head CT revealed that left epidural hemorrhage. But this time we just gave non-operative treatment and especially added the dose of glucocorticosteroid. 12 days later, the patient's symptoms were under control and she was discharged from hospital. We also reviewed the literature about spontaneous epidural hemorrhage and bilateral epidural hematomas.