Focal Point of Fanconi Anemia Signaling.

Among human genetic diseases, Fanconi Anemia (FA) tops all with its largest number of health complications in nearly all human organ systems, suggesting the significant roles played by FA genes in the maintenance of human health. With the accumulated research on FA, the encoded protein products by FA genes have been building up to the biggest cell defense signaling network, composed of not only 22+ FA proteins but also ATM, ATR, and many other non-FA proteins. The FA D2 group protein (FANCD2) and its paralog form the focal point of FA signaling to converge the effects of its upstream players in response to a variety of cellular insults and simultaneously with downstream players to protect humans from contracting diseases, including aging and cancer. In this review, we update and discuss how the FA signaling crucially eases cellular stresses through understanding its focal point.

MIB1 upregulates IQGAP1 and promotes pancreatic cancer progression by inducing ST7 degradation.

Despite recent progress in cancer treatment, the prognosis of patients with pancreatic cancer still remains poor. Pancreatic tumors are reported to display high molecular heterogeneity. Elucidating the molecular mechanisms underlying pancreatic cancer progression is essential for improving patient treatment and survival. The overexpression of E3 ubiquitin ligase mind bomb 1 (MIB1) was previously described in pancreatic cancer cells, where it enhanced tumor cell proliferation. However, the role of MIB1 in pancreatic cancer progression remains elusive. In the present study, we confirmed that MIB1 expression is elevated in pancreatic cancer tissues and that high levels of MIB associate with unfavorable prognosis. Overexpression of MIB1 enhanced proliferation and invasion of pancreatic cancer cells both in vitro and in vivo. We further investigated the molecular mechanisms downstream of MIB1 and observed for the first time that MIB1 targets suppressor of tumorigenicity 7 protein (ST7), previously described as suppressor of tumorigenicity, for proteasomal degradation. Furthermore, we found that ST7 suppressed tumor growth by downregulating IQ motif containing GTPase activating protein 1 (IQGAP1) in pancreatic tumor cells. Thus, these data show that MIB1 promotes pancreatic cancer progression by inducing ST7 degradation followed by downregulation of IQGAP1 in pancreatic cancer cells. In conclusion, our research shows that the MIB1/ST7/IQGAP1 axis is essential for pancreatic cancer progression, and MIB1 inhibition may serve as a novel therapeutic strategy in patients with pancreatic cancer.

Effects of Severe Acute Respiratory Syndrome Coronavirus 2 Infection on Pregnant Women and Their Infants.

CONTEXT.­: The pandemic of a novel coronavirus, termed severe acute respiratory syndrome coronavirus 2 (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 in Wuhan from January 20 to March 19, 2020, were included. Detailed clinical data of those pregnancies with COVID-19 were retrospectively collected and analyzed. RESULTS.­: Twenty-seven pregnant women (4 early pregnancies included) with laboratory or clinically confirmed SARS-CoV-2 infection and 24 neonates born to the 23 women in late pregnancy were analyzed. On admission, 46.2% (13 of 27) of the patients had symptoms, including fever (11 of 27), cough (9 of 27), and vomiting (1 of 27). Decreased total lymphocytes count was observed in 81.5% (22 of 27) of patients. Twenty-six patients showed typical viral pneumonia by chest computed tomography scan, whereas 1 patient confirmed with COVID-19 infection showed no abnormality on chest computed tomography. One mother developed severe pneumonia 3 days after her delivery. No maternal or perinatal death occurred. Moreover, 1 early preterm newborn born to a mother with the complication of premature rupture of fetal membranes, highly suspected to have SARS-CoV-2 infection, was SARS-CoV-2 negative after repeated real-time reverse transcriptase polymerase chain reaction testing. Statistical differences were observed between the groups of women in early and late pregnancy with COVID-19 in the occurrence of lymphopenia and thrombocytopenia. CONCLUSIONS.­: No major complications were reported among the studied cohort, though 1 serious case and 1 perinatal infection were observed. Much effort should be made to reduce the pathogenic effect of COVID-19 infection in pregnancies.

CDK5/FBW7-dependent ubiquitination and degradation of EZH2 inhibits pancreatic cancer cell migration and invasion.

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 bona fide 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.

Overexpression of G protein-coupled receptor GPR87 promotes pancreatic cancer aggressiveness and activates NF-κB signaling pathway.

BACKGROUND: Pancreatic 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. METHODS: GPR87 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. RESULTS: Herein, 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. CONCLUSIONS: Our findings suggest that GPR87 plays a critical oncogenic role in pancreatic cancer progression and highlight its potential as a target for pancreatic cancer therapy.

Mutations in the p16 gene in DMBA-induced pancreatic intraepithelial neoplasia and pancreatic cancer in rats.

BACKGROUND: 7, 12-dimethylbenzanthracene (DMBA)-induced pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic cancer. However, this model has not been characterized genetically, and in particular, the major genetic alterations in the p16 gene are unknown. METHODS: Lesions of PanIN and pancreatic cancer were induced with DMBA implantation in 40 rats, and control pancreatic tissue was obtained from 10 age-matched rats without exposure to DMBA. Pancreatic tissue was harvested three months after DMBA implantation and DNA was extracted. Homozygous deletions and point mutations of the p16 (exons 1 and 2) gene were detected by PCR amplification and direct sequencing. RESULTS: DMBA implantation in the 40 rats induced 26 PanINs and 9 carcinomas. The overall frequency of p16 alterations in the pancreatic tissue of these rats was 42.86% (15/35), and the changes were point mutations, not homozygous deletions. p16 mutations were present in 30.77% (8/26) of the rats with PanIN and 77.78% (7/9) of the rats with carcinoma (P<0.05). The increasing incidence of p16 alterations was detected in 20.00% (1/5) of PanIN-1, 28.57% (2/7) of PanIN-2 and 35.71% (5/14) of PanIN-3 lesions. CONCLUSION: Our findings indicated that p16 alteration is a common event in the carcinogenesis of this model and that the mutation pattern is analogous to that of human lesions.

Contribution of murine bone marrow mesenchymal stem cells to pancreas regeneration after partial pancreatectomy in mice.

The implantation of BMSCs (bone marrow mesenchymal stem cells) has emerged as a potential method of treating tissue damage, but the in vivo differentiation of BMSCs in an injured pancreas and its therapeutic effects have not been determined. Our aim has been to investigate the potential of BMSCs to contribute to the parenchyma and mesenchymal components of the pancreas during rapid regeneration, with preliminary exploration of the molecular mechanisms of this process. GFP(+) (green fluorescent protein(+) ) BMSCs were intravenously infused into the tail veins of mice that had received a 65-70% partial pancreatectomy, while mice that had only received a partial pancreatectomy and mice that had only been injected with BMSCs served as controls. Four weeks later, the injected GFP(+) BMSCs were diffusely engrafted in the pancreatic parenchyma and mesenchyma of the recipient mice with pancreatic injuries and had differentiated into pancreatic ductal epithelial cells (accounting for 1.7±0.3%), vascular endothelial cells (3.2±0.6%) and PSCs (pancreatic stellate cells) (5.2±1.6%), but no ß or neural cells. Significantly, more engrafted and differentiated GFP(+) BMSCs were observed in the regenerating pancreas than in the normal pancreas. For the mice that received a partial pancreatectomy, the pancreatic weight/body weight of the mice with BMSC treatment was greater than mice without BMSC treatment (P<0.05). In addition, real-time RT-PCR (reverse transcription-PCR) showed that the expression levels of miR-9 (microRNA 9) and miR-204 in the engrafted BMSCs (5.2- and 2.6-fold, P<0.05, respectively) were increased compared with wild-type BMSCs. We also observed a significant reduction in the expression of miR-375 (0.71-fold, P<0.05) in engrafted GFP(+) BMSCs compared with wild-type BMSCs. BMSCs can therefore be a potential cell bank for treating pancreatic injuries by contributing to a variety of cell types. This process might be related to the expression of miR-9, miR-204 and miR-375.