Pancreatic cancer is one of the most lethal cancer types. Enhancer of zeste homolog 2 (EZH2) is an oncogenic protein overexpressed in pancreatic cancer, and EZH2 could be a potential therapeutic target for the treatment of pancreatic cancer. Although significant progress has been made toward understanding the function and deregulation of EZH2 in cancer cells, the posttranslational regulation of EZH2 in cancer cells is still unclear. F-box and WD repeat domain-containing 7 (FBW7) acts as a tumor suppressor by targeting multiple oncoprotein substrates for ubiquitination and degradation. Here we demonstrate that EZH2 is a substrate of FBW7 in pancreatic cancer cells. We provide evidence that the activated CDK5 kinase is involved in the EZH2 phosphorylation that is required for FBW7-mediated degradation. We further show that FBW7 suppresses EZH2 activity and inhibits tumor migration and invasion via degradation of EZH2 in pancreatic cancer cells. Furthermore, immunohistochemistry analysis revealed that expression of EZH2 protein negatively correlates with FBW7 protein levels in a cohort of human pancreatic cancer specimens. Collectively, our findings demonstrate that FBW7 is a novel E3 ligase of EZH2 that regulates the EZH2 protein level in pancreatic cancer and represents a viable strategy for effective treatment of pancreatic cancer.

BackgroundPancreatic cancer is a highly lethal disease and has the worst prognosis of any major malignancy. G protein-coupled receptor GPR87 is reported to be overexpressed in multiple cancers. The clinical significance and biological role of GPR87 in pancreatic cancer, however, remain to be established.MethodsGPR87 expression in pancreatic cancer cell lines, paired patient tissues were determined using western blotting and Real-time PCR. Ninety-six human pancreatic cancer tissue samples were analyzed by immunochemistry (IHC) to investigate the association between GPR87 expression and the clinicopathological characteristics of pancreatic cancer. Functional assays, such as anchorage-independent growth, chicken chorioallantoic membrane (CAM) assay, transwell matrix penetration assay, and Annexin V-FITC and PI staining and a xenograft tumor model were used to determine the oncogenic role of GPR87 in human pancreatic cancer progression. The effect of GPR87 on NF-κB signaling pathway was further investigated using the luciferase reporter assays, and by detection of the NF-κB signaling downstream genes.ResultsHerein, we reported that GPR87 was markedly overexpressed in pancreatic cancer cells and clinical tissues. Immunohistochemical analysis showed that the expression of GPR87 significantly correlated with patients’ clinicopathologic features, including clinical stage and tumor-nodule-metastasis (TNM) classification. Pancreatic cancer patients with higher levels of GPR87 expression had shorter overall survival compared to patients with lower GPR87 levels. We gained valuable insights into the mechanism of GPR87 expression in pancreatic cancer cells by demonstrating that overexpressing GPR87 significantly enhanced, whereas silencing endogenous GPR87 inhibited, the proliferation, angiogenesis and increased resistance to gemcitabine-induced apoptosis of pancreatic cancer in vitro and tumorigenicity of pancreatic cancer cells in vivo. Finally, we demonstrated that GPR87 enhanced pancreatic cancer aggressiveness by activating NF-κB signaling pathway. Conclusions: Taken together, these findings suggest that GPR87 plays a critical oncogenic role in pancreatic cancer progression and highlight its potential as a target for pancreatic cancer therapy.ConclusionsOur findings suggest that GPR87 plays a critical oncogenic role in pancreatic cancer progression and highlight its potential as a target for pancreatic cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0627-6) contains supplementary material, which is available to authorized users.

Context: The pandemic of a novel coronavirus, termed SARS-CoV-2, has created an unprecedented global health burden. Objective: To investigate the effect of the SARS-CoV-2 infection on maternal, fetal, and neonatal morbidity and other poor obstetrical outcomes. Design: All suspected cases of pregnant women with Coronavirus Disease 2019 (COVID-19) admitted into one center of Wuhan from Jan 20, 2020 to March 19, 2020 were included. Detailed clinical data of those pregnancies with COVID-19 were retrospectively collected and analyzed. Results: Twenty-seven laboratory or clinically confirmed SARS-CoV-2 infection pregnant women (4 early pregnancies included) and 24 neonates born to the 23 late pregnant mothers were analyzed. On admission, 46.2% (13/27) of the patients had symptoms, including fever (11/27), cough (9/27) and vomiting (1/27). Decreased total lymphocytes count was observed in 81.6% (22/27) patients. Twenty-six patients showed typical viral pneumonia by chest computed tomography (CT) scan, while one patient confirmed with COVID-19 infection showed no abnormality on chest CT. One mother developed severe pneumonia three days after her delivery. No maternal and perinatal death occurred. Moreover, one early preterm newborn, born to a mother with complication of premature rupture of fetal membranes, highly suspected with SARS-CoV-2 infection, was SARS-CoV-2 negative after repeated real-time reverse transcriptase polymerase chain reaction testing. Statistical difference was observed between the groups of early pregnant and late pregnant women with COVID-19 in the occurrence of lymphopenia and thrombocytopenia. Conclusions: No major complication were reported among the studied cohort, though one serious case and one perinatal infection were observed. Much effort should be done to reduce the pathogenic effect of COVID-19 infection in pregnancies.