Due to the large proportion of BRCA deficiency and chromosomal instability in OS patients, poly (ADP-ribose) polymerase inhibitors (PARPi) could be an effective strategy for anti-OS therapy.In two orthotopic OS mouse models, we discovered that although PARPi had inhibitory effect on the growth of the orthotopic OS tumors regardless of BRCA deficiency, the treatment of PARPi essentially aggravated the pulmonary metastasis of OS in both models.A protein playing a crucial role in OS metastasis, ezrin, was identified as an interactive protein for PARP1.The phosphorylation of ezrin was significantly promoted during PARP inhibition.Besides the traditional function of phosphorylated ezrin at plasma membrane, we newly identified its nuclear speckle localization and its function with mRNA export.Ezrin knockdown or phosphorylation inhibition could partially rescue PARPi induced metastasis.Collectively, we unveiled a new mechanism for PARP-involved OS metastasis, which proposed a novel combinational therapy strategy using PARP and ezrin inhibitors for future OS treatment.
Objective This paper aimed to assess the physiological effects of p53 on glucose homeostasis in vivo. Methods A recombinant adenoviral p53 (rAd-p53) vector was administered to insulin-resistant diabetic mice. Intraperitoneal glucose tolerance test was performed in all groups of mice. Changes in fasting blood glucose, serum triglycerides, C-peptide, and insulin concentrations in treated and untreated mice were measured. Analyses of the target genes related to glucose metabolism were performed. Results Treatment with the rAd-p53 improved glucose control in a dose- and time-dependent manner and lowered significantly the fasting blood glucose, the serum triglycerides, and improved tolerance test of glucose as compared to control. Lowered blood glucose was associated with up-regulation of genes in the glycogenesis pathways, and down-regulation of genes in the gluconeogenesis pathways in the liver. Overexpressions of GLUT2, GK, PPAR-γ, and insulin receptor precursor were also observed in the liver and the pancreas of treated animals. Conclusions Activation of p53-mediated glucose metabolism led to insulin-like antidiabetic effect in the mouse model especially by changing hepatic insulin sensitivity in the diabetic mouse model.
Objective The aim of this study was to investigate the role of LONP1 in the progression of pancreatic cancer. Methods Lentivirus was used to silence LONP1 in PANC-1 cells. Colony formation assay, cell counting kit (CCK8) assay, cell scratch-wound assay, and transwell assay were used to assess the effects of our strategy on inhibiting cancer growth, migration, and invasion. Protein expression was detected by Western blot analysis. Results The expression of LONP1 in pancreatic carcinoma tissues was higher than that in adjacent normal pancreatic tissues. Downregulation of LONP1 suppressed the proliferation, migration, and invasion of PANC-1 cells. Knockdown of LONP1 in PANC-1 cells inhibited epithelial-mesenchymal transition and matrix metalloprotein (MMP) 2/9 by downregulation of vimentin, snail, slug, MMP2, and MMP9 and upregulation of claudin-1. The c-Jun N-terminal kinase pathway was inactivated in LONP1 knockdown PANC-1 cells. Activation of the c-Jun N-terminal kinase pathway by anisomycin treatment significantly reversed the changes in epithelial-mesenchymal transition markers and MMP2/9 induced by ablation of LONP1 in PANC-1 cells. Conclusions LONP1 plays a vital role in the proliferation and metastasis of pancreatic cancer, which provides a potential therapeutic target for the treatment of pancreatic cancer.
Abstract To explore the mechanism of coadaptation and the potential drivers of pancreatic ductal adenocarcinoma (PDAC) metastasis to the liver, we study key molecules involved in this process and their translational value. Premetastatic niche (PMN) and macrometastatic niche (MMN) formation in a mouse model is observed via CT combined with 3D organ reconstruction bioluminescence imaging, and then we screen slit guidance ligand 2 (SLIT2) and its receptor roundabout guidance receptor 1 (ROBO1) as important factors. After we confirm the expression and distribution of SLIT2 and ROBO1 in samples from PDAC patients and several mouse models, we discover that SLIT2-ROBO1-mediated coadaptation facilitated the implantation and outgrowth of PDAC disseminated tumour cells (DTCs) in the liver. We also demonstrate the dependence receptor (DR) characteristics of ROBO1 in a follow-up mechanistic study. A neutralizing antibody targeting ROBO1 significantly attenuate liver metastasis of PDAC by preventing the coadaptation effect. Thus, we demonstrate that coadaptation is supported by the DR characteristics in the PMN and MMN.
Early diagnosis and prevention is a key factor in reducing the mortality and morbidity of cancer. However, currently available screening tools lack enough sensitivity for early diagnosis. It is important to develop noninvasive techniques and methods that can screen and identify asymptomatic patients who have cancer. Biomarkers of cancer status can also serve as powerful tools in monitoring the course of cancer and in determining the efficacy and safety of novel therapies. Thus, discovery of novel specific biomarkers are needed that may provide informative clues for early diagnosis and treatment of cancer. Recently, remarkable progress has been made in the development of new proteomics technology. The progress that has been made in this field is helpful in identifying biomarkers that can be used for early diagnosis of cancer and improving the understanding of the molecular etiological mechanism of cancer. This article describes the current state of the art in this field.
A grim prognosis of pancreatic cancer (PCa) was attributed to the difficulty in early diagnosis of the disease. Identifying novel biomarkers for early detection of PCa is thus urgent to improve the overall survival rates of patients. The study was performed firstly by identification of candidate microRNAs (miRNAs) in formalin-fixed, paraffin-embedded tissues using microarray profiles, and followed by validation in a serum-based cohort study to assess clinical utility of the candidates. In the cohorts, a total of 1273 participants from four centers were retrospectively recruited as two cohorts including training and validation cohort. The collected serum specimens were analyzed by real-time polymerase chain reaction. We identified 27 miRNAs expressed differentially in PCa tissues as compared to the benign. Of which, the top-four was selected as a panel whose diagnostic efficacy was fully assessed in the serum specimens. The panel exhibited superior to CA19-9, CA125, CEA and CA242 in discriminating patients with early stage PCa from healthy controls or non-PCa including chronic pancreatitis as well as pancreatic cystic neoplasms, with the area under the curves (AUC) of 0.971 (95% CI 0.956–0.987) and 0.924 (95% CI 0.899–0.949), respectively. Moreover, the panel eliminated interference from other digestive tumors with a specificity of 90.2%. A panel of four serum miRNAs was developed showing remarkably discriminative ability of early stage PCa from either healthy controls or other pancreatic diseases, suggesting it may be developed as a novel, noninvasive approach for early screening of PCa in clinic.
Abstract Oral squamous cell carcinoma (OSCC) remains the sixth most common human cancer with high mortality rate worldwide. Understanding the molecular mechanisms is important for development of an effective treatment for the disease. MicroRNA is a short, noncoded nucleotide playing an important role in tumorigenesis and metastasis. This study is to identify novel microRNAs and their targets in order to understand the molecular mechanisms underlying OSCC and metastasis using label-free proteomics and microRNA microarray techniques. Human oral tissue biopsies from three groups of subjects who had benign, localized carcinoma and distal carcinoma were collected from the archived tissue bank at Pathology in Creighton University. Total RNA and proteins were extracted from the core biopsy of the same subject. MicroRNA identification was performed by using Affymetrix GeneChip miRNA arrays and comprehensive data analysis. Protein was analyzed by using label-free LTQ orbit trap mass spectrometry. Forty-four miRNAs were upregulated significantly, including let-7b, miR-720, miR-21, and miR-1274b, while 41 miRNAs were remarkably downregulated, including miR-195, and miR-932, at localized and distal carcinoma compared to benign tissues. Additionally, as compared to benign, 38 miRNAs upregulated at local carcinoma were downregulated significantly at distal carcinoma, while other 17 miRNAs downregulated significantly at localized carcinoma were upregulated gigantically at distal carcinoma. Those miRNAs were further validated by qRT-PCR and FISH. Among those upregulated at both local and distal, miR-720 was further studied, and tryptase alpha-1 as its target was identified. MicroRNA-720 mimics suppressed significantly the expression of tryptase alpha-1 in cultured human OSCC stem cell lines. Results from miR-720 tissue microarray analysis showed that 98.8% of sensitivity and 100% of specificity for OSCC detection were achieved, suggesting that miR-720 may be developed as a novel biomarker for detection of human OSCC. Citation Format: Gary Guishan Xiao, Min Cao. MicroRNA regulation of oral squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 487.
A large body of evidence has shown that exposure to ambient particulate matter (PM) leads to asthma exacerbation through an excitation of allergic inflammation. Utilizing diesel exhaust particles (DEPs) as a model air pollutant, we and others have demonstrated that PM contains redox-active chemicals that generate inflammation through an oxidative stress mechanism. Recently, the strengths of proteomics have enabled us to demonstrate that organic DEP extracts induce a hierarchical expression pattern of oxidative stress-induced proteins in macrophages and epithelial cells. As a further extension of this work, we now employ a new phosphosensor fluorescent dye, Pro-Q Diamond, to elucidate the induction of phosphoproteins and intracellular signaling cascades that may play a role in DEP-induced inflammation. We demonstrate that DEPs induced the phosphorylation of several phosphoproteins that belong to a number of signaling pathways as well as other oxidative stress pathways. In combination with cytokine array, phosphoproteome analysis using Pro-Q Diamond allowed us to characterize the aromatic and polar chemicals of DEPs that are involved in the activation of three different mitogen-activated protein (MAP) kinase signaling pathways.
MicroRNAs (miRNAs) play an important regulatory role in breast tumorigenesis. Previously, we found that let-7 miRNAs were downregulated significantly in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. In this study, we further found that endogenous levels of let-7b and let-7i miRNAs are inversely correlated with levels of estrogen receptor (ER)-a36, a new variant of ER-α66, in the FFPE tissue set. Bioinformatic analysis suggested that ER-α36 may be another target of let-7 miRNAs. To test this hypothesis, cotransfection of let-7 mimics or inhibitors together with full-length or a fragment of ER-α36 3′UTR luciferase construct was performed, and we found that let-7b and let-7i mimics suppressed the activity of reporter gene significantly, which was enhanced remarkably by let-7b and let-7i inhibitors. Both mRNA and protein expression of ER-α36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Furthermore, ER-α36 mediated nongenomic MAPK and Akt pathways were weakened by let-7b and let-7i mimics in triple negative breast cancer cell line MDA-MB-231. The reverse correlation between let-7 miRNAs and ER-α36 also exists in Tamoxifen (Tam)-resistant MCF7 cell line. Transfection of let-7 mimics to Tam-resistant MCF7 cells downregulated ER-α36 expression and enhanced the sensitivity of MCF7 cells to Tam in estrogen-free medium, which could be restored by overexpression of ER-α36 constructs without 3′UTR. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-α36 mediated nongenomic estrogen signal pathways and Tam resistance.
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