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Cancer Biology
Usp5 functions as an oncogene for stimulating tumorigenesis in hepatocellular carcinoma
Apr 21, 2017   Oncotarget
Liu Y, Wang WM, Lu YF, Feng L, Li L, Pan MZ, Sun Y, Suen CW, Guo W, Pang JX, Zhang JF, Fu WM
Usp5 functions as an oncogene for stimulating tumorigenesis in hepatocellular carcinoma
Apr 21, 2017
Oncotarget
As deubiquitinases, several ubiquitin specific protease members have been reported to mediate tumorigenesis. Although ubiquitin specific protease 5 (Usp5) was previously demonstrated to suppress p53 transcriptional activity and DNA repair, its role in carcinogenesis remains elusive. In this study, we sought to define a novel role of Usp5 in tumorigenesis. It was found that Usp5 was significantly upregulated in hepatocellular carcinoma (HCC) cells and most clinical specimens. Further functional investigation also showed that Usp5 knockdown suppressed cell proliferation, migration, drug resistance and induced apoptosis; on the other hand, Usp5 overexpression promoted colony formation, migration, drug resistance and tumorigenesis. Additionally, the inactivated p14ARF-p53 signaling was observed in Usp5 overexpressed HCC cells, while this signaling was activated by Usp5 knockdown. Therefore, our data demonstrated that Usp5 contributed to hepatocarcinogenesis by acting as an oncogene, which provides new insights into the pathogenesis of HCC and explores a promising molecular target for HCC diagnosis and therapy.
miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response
Apr 22, 2017   Blood
Wallace JA, Kagele DA, Eiring AM, Kim CN, Hu R,   . . . . . .   , Rao DS, Miles RR, Round JL, Deininger MW, O'Connell RM
miR-155 promotes FLT3-ITD-induced myeloproliferative disease through inhibition of the interferon response
Apr 22, 2017
Blood
FLT3-ITD+ AML accounts for approximately 25% of all AML cases, and is a subtype that carries a poor prognosis. miR-155 is specifically overexpressed in FLT3-ITD+ AML compared to FLT3-WT AML, and is critical for the growth of FLT3-ITD+ AML cells in vitro. However, miR-155's role in regulating FLT3-ITD-mediated disease in vivo remains unclear. In this study, we utilized a genetic mouse model to determine whether miR-155 influences the development of FLT3-ITD-induced myeloproliferative disease. Results indicate that miR-155 promotes FLT3-ITD-induced myeloid expansion in the bone marrow, spleen, and peripheral blood. Mechanistically, miR-155 increases proliferation of the hematopoietic stem and progenitor cell compartments by reducing the growth-inhibitory effects of the interferon response, and this involves targeting of Cebpb. Consistent with our observations in mice, primary FLT3-ITD+ AML clinical samples have significantly higher miR-155 levels and a lower interferon response compared to FLT3-WT AML samples. Further, inhibition of miR-155 in FLT3-ITD+ AML cell lines using CRISPR/Cas9, or primary FLT3-ITD+ AML samples using LNA antisense inhibitors, results in an elevated interferon response and reduces colony formation. Altogether, our data reveal that miR-155 collaborates with FLT3-ITD to promote myeloid cell expansion in vivo, and that this involves a multi-target mechanism that includes repression of interferon signaling. Copyright © 2017 American Society of Hematology.
miR-24-3p Is Overexpressed in Hodgkin Lymphoma and Protects Hodgkin and Reed-Sternberg Cells from Apoptosis
Apr 22, 2017   The American Journal Of Pathology
Yuan Y, Kluiver J, Koerts J, de Jong D, Rutgers B, Razak FRA, Terpstra M, Plaat B, Nolte IM, Diepstra A, Visser L, Kok K, van den Berg A
miR-24-3p Is Overexpressed in Hodgkin Lymphoma and Protects Hodgkin and Reed-Sternberg Cells from Apoptosis
Apr 22, 2017
The American Journal Of Pathology
miRNAs play important roles in biological processes, such as proliferation, metabolism, differentiation, and apoptosis, whereas altered expression levels contribute to diseases, such as cancers. We identified miRNAs with aberrant expression in Hodgkin lymphoma (HL) and investigated their role in pathogenesis. Small RNA sequencing revealed 84 significantly differentially expressed miRNAs in HL cell lines as compared to germinal center B cells. Three up-regulated miRNAs-miR-23a-3p, miR-24-3p, and miR-27a-3p-were derived from one primary miRNA transcript. Loss-of-function analyses for these miRNAs and their seed family members resulted in decreased growth on miR-24-3p inhibition in three and of miR-27a/b-3p inhibition in one HL cell line. Apoptosis analysis indicated that the effect of miR-24-3p on cell growth is at least in part caused by an increase of apoptotic cells. Argonaute 2 immunoprecipitation revealed 1142 genes consistently targeted by miRNAs in at least three of four HL cell lines. Furthermore, 52 of the 1142 genes were predicted targets of miR-24-3p. Functional annotation analysis revealed a function related to cell growth, cell death, and/or apoptosis for 15 of the 52 genes. Western blotting of the top five genes showed increased protein levels on miR-24-3p inhibition for CDKN1B/P27kip1 and MYC. In summary, we showed that miR-24-3p is up-regulated in HL and its inhibition impairs cell growth possibly via targeting CDKN1B/P27kip1 and MYC. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Comprehensive two-dimensional PC-3 prostate cancer cell membrane chromatography for screening anti-tumor components from Radix Sophorae flavescentis
Apr 22, 2017   Journal Of Separation Science
Wang Q, Xu J, Li X, Zhang D, Han Y, Zhang X
Comprehensive two-dimensional PC-3 prostate cancer cell membrane chromatography for screening anti-tumor components from Radix Sophorae flavescentis
Apr 22, 2017
Journal Of Separation Science
Radix Sophorae flavescentis is generally used for the treatments of different stages of prostate cancer in China. It has ideal effects when combined with surgical treatment and chemotherapy. However, its active components are still ambiguous. We devised a comprehensive two-dimensional PC-3 prostate cancer cell membrane chromatography system for screening anti-prostate cancer components in Radix Sophorae flavescentis. Gefitinib and dexamethasone were chosen as positive and negative drugs respectively for validation and optimization the selectivity and suitability of the comprehensive two-dimensional chromatographic system. Five compounds, sophocarpine, matrine, oxymatrine, oxysophocarpine and xanthohumol were found to have significant retention behaviors on the PC-3 cell membrane chromatography and were unambiguously identified by time-of-flight mass spectrometry. Cell proliferation and apoptosis assays confirmed that all five compounds had anti-prostate cancer effects. Matrine and xanthohumol had good inhibitory effects, with half maximal inhibitory concentration values of 0.893 and 0.137 mg/mL, respectively. Our comprehensive two-dimensional PC-3 prostate cancer cell membrane chromatographic system promotes the efficient recognition and rapid analysis of drug candidates, and it will be practical for the discovery of prostate cancer drugs from complex traditional Chinese medicines. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Prognostic impact of PD-1 and its ligands in renal cell carcinoma
Apr 22, 2017   Medical Oncology (Northwood, London, England)
Erlmeier F, Weichert W, Schrader AJ, Autenrieth M, Hartmann A, Steffens S, Ivanyi P
Prognostic impact of PD-1 and its ligands in renal cell carcinoma
Apr 22, 2017
Medical Oncology (Northwood, London, England)
Programmed death-1 receptor (PD-1) and programmed death-1 receptor-ligand (PD-L1) have been suggested to play a role as prognostic markers in clear cell renal cell carcinoma (ccRCC). The association between PD-L1 and prognosis seems to be more robust than for PD-1. Further, preliminary analyses suggest that neither PD-1 nor its ligands play a role as prognostic markers in non-clear cell RCC, while the prognostic role of PD-L2 in ccRCC as well as in non-clear cell RCC remains unclear.
Micropapillary bladder cancer: a clinico-pathological characterization and treatment analysis
Apr 22, 2017   Clinical & Translational Oncology : Official Publication Of The Federation Of Spanish Oncology Societies And Of The National Cancer Institute Of Mexico
Li Z, Liao H, Tan Z, Mao D, Wu Y, Xiao YM, Yang SK, Zhong L
Micropapillary bladder cancer: a clinico-pathological characterization and treatment analysis
Apr 22, 2017
Clinical & Translational Oncology : Official Publication Of The Federation Of Spanish Oncology Societies And Of The National Cancer Institute Of Mexico
Micropapillary bladder cancer (MPBC) is a very rare and aggressive variant of urothelial carcinoma (UC). The aim of this study was to investigate the clinico-pathological characteristics, treatment, and prognosis of MPBC to improve the understanding of this invasive disease. We reviewed the records of 6 patients with MPBC who were evaluated and treated at our hospital between 2009 and 2015, and additionally reviewed 38 cases reported in the literature. In 44 cases, 36 cases (81.8%) were male and 8 cases (18.2%) were female, with a male:female ratio of 4.5:1; the median age of the patients was 68 years (range 45-91 years). A majority (81.8%) of patients with cT1 above or with lymph node and distant metastasis (cT2N0 in 18.2%, cT3-4N0 in 13.6%, cTanyN+ in 43.2%, and cTanyM+ in 6.8%). There was a high grade in 70.5% of patients. Lymphovascular invasion (LVI) was present in 61.4% of patients, and LVI in cT2 was more common than in cT1 (71.4 vs 22.2%). 52.3% of patients were treated with radical cystectomy (RC). After a mean follow-up of 16.2 months, 77.3% of patients developed distant metastases, and 47.7% of patients died of the disease. The mean overall survival (OS) was 28.9 months and the median OS was 20 months, and the amount of micropapillary (MPP) is correlated inversely with prognosis. Micropapillary bladder cancer is a rare variant of UC associated with a poor prognosis, which often presents at an advanced stage with LVI and distant metastases. The optimal treatment strategy is early RC combined with chemotherapy.
Ginseng-derived panaxadiol saponins promote hematopoiesis recovery in cyclophosphamide-induced myelosuppressive mice: Potential novel treatment of chemotherapy-induced cytopenias
Apr 22, 2017   Chinese Journal Of Integrative Medicine
Sun X, Zhao YN, Qian S, Gao RL, Yin LM, Wang LP, Chong BH, Zhang SZ
Ginseng-derived panaxadiol saponins promote hematopoiesis recovery in cyclophosphamide-induced myelosuppressive mice: Potential novel treatment of chemotherapy-induced cytopenias
Apr 22, 2017
Chinese Journal Of Integrative Medicine
To investigate the potential efficacy of panaxadiol saponins component (PDS-C), a biologically active fraction isolated from total ginsenosides, to reverse chemotherapy-induced myelosuppression and pancytopenia caused by cyclophamide (CTX). Mice with myelosuppression induced by CTX were treated with PDS-C at a low- (20 mg/kg), moderate- (40 mg/kg), or high-dose (80 mg/kg) for 7 consecutive days. The level of peripheral white blood cell (WBC), neutrophil (NEU) and platelet (PLT) were measured, the histopathology and colony formation were observed, the protein kinase and transcription factors in hematopoietic cells were determined by immunohistochemical staining and Western blot. In response to PDS-C therapy, the peripheral WBC, NEU and PLT counts of CTX-induced myelosuppressed mice were significantly increased in a dose-dependent manner. Similarly, bone marrow histopathology examination showed reversal of CTX-induced myelosuppression with increase in overall bone marrow cellularity and the number of hematopoietic cells (P
The Pretreatment Neutrophil-to-Lymphocyte Ratio is a Prognostic Determinant of T3-4 Hypopharyngeal Squamous Cell Carcinoma
Apr 22, 2017   Annals Of Surgical Oncology
Lo WC, Wu CT, Wang CP, Yang TL, Lou PJ, Ko JY, Chang YL
The Pretreatment Neutrophil-to-Lymphocyte Ratio is a Prognostic Determinant of T3-4 Hypopharyngeal Squamous Cell Carcinoma
Apr 22, 2017
Annals Of Surgical Oncology
This study aimed to investigate the clinicopathological factors that influence recurrence and survival in patients who undergo operations for T3-4 hypopharyngeal squamous cell carcinomas (SCCs). One hundred and five patients who underwent surgery between 2001 and 2008 for advanced hypopharyngeal SCCs were consecutively enrolled and reviewed. The pretreatment neutrophil-to-lymphocyte ratio (NLR; median 3.22, range 0.62-46.50) was associated with disease recurrence and patient survival. A difference in the 5-year cumulative disease recurrence rate between patients with high (≥3.22) and low (
Novel esophageal stent for treatment of cervical anastomotic leakage after esophagectomy
Apr 22, 2017   Surgical Endoscopy
Wu G, Yin M, Zhao YS, Fang Y, Zhao G, Zhao J, Han X
Novel esophageal stent for treatment of cervical anastomotic leakage after esophagectomy
Apr 22, 2017
Surgical Endoscopy
Dedicated stents for treatment of cervical anastomotic leakage are currently unavailable. In this study, we aimed to assess the feasibility and efficacy of using custom-designed stents for treatment of cervical anastomotic leakage after esophagectomy. The stents were designed according to the location and size of the leakage and the residual esophageal length as determined by esophagography in each case. It had a cup-shaped upper end and a globular lower end and a total height of 60-85 mm. The diameter of the upper cup-shaped part was 24-26 mm and the length 20-25 mm. The cup part and the stent main body were connected at a right angle. Data from cervical anastomotic leakage patients treated with these stents were retrospectively analyzed. Data from a total of 27 patients with cervical anastomotic leakage were retrospectively analyzed. The custom-designed esophageal covered stents were placed successfully at the first attempt in 24 cases (88.9%). The total operative time was 5-15 min. The stents were removed 7 days to 3 months after leakage healing. Follow-up showed no leakage recurrence; three patients had anastomosis scar strictures. Fifteen patients died (median survival 13.4 months) and nine survived. Placement of the novel esophageal covered stent is a minimally invasive, efficacious treatment option for the patients with cervical anastomotic leakage after esophagectomy.
Knockdown of PRDX2 Sensitizes Colon Cancer Cells to 5-FU by Suppressing the PI3K/AKT Signaling Pathway
Apr 22, 2017   Bioscience Reports
Xu J, Zhang S, Wang R, Wu X, Zeng L, Fu Z
Knockdown of PRDX2 Sensitizes Colon Cancer Cells to 5-FU by Suppressing the PI3K/AKT Signaling Pathway
Apr 22, 2017
Bioscience Reports
Although, 5-Fluorouracil (5-FU) remains widely used in adjuvant therapy in patients with colon cancer, resistance to 5-FU-based chemotherapy is an important reason for treatment failure. Recent studies have reported that an enhanced reactive oxygen species (ROS) scavenging system shows drug resistance to 5-FU. Peroxiredoxin-2 (PRDX2), is an important member of the ROS scavenging system, and may be a potential target that promotes chemosensitivity to 5-FU in colon cancer. Here, we depleted PRDX2 by PRDX2-shRNA-LV transduction in two colon cancer cell lines and found that in vitro PRDX2 knockdown facilitates cell death and apoptosis in 5-FU-treated colon cancer cells. In addition, we found that PRDX2 depletion in mice treated with 5-FU resulted in, inhibition of tumor growth, compared to mice treated with 5-FU alone. Our data also suggested that the PI3K/AKT signaling pathway links PRDX2 with 5-FU-induced apoptosis in colon cancer. Furthermore, when PRDX2 was overexpressed in colon cancer cells, we found increased p-AKT protein expression and reduced Bcl-2/Bax protein expression. PRDX2 and p-AKT protein expression were analyzed by immunohistochemistry technology in human colon carcinoma tissues. Pearson Correlation Coefficient is 0.873 and p
Dual histone reader ZMYND8 inhibits cancer cell invasion by positively regulating epithelial genes
Apr 22, 2017   The Biochemical Journal
Basu M, Sengupta I, Khan W, Srivastava DK, Chakrabarti P, Roy S, Das C
Dual histone reader ZMYND8 inhibits cancer cell invasion by positively regulating epithelial genes
Apr 22, 2017
The Biochemical Journal
Enhanced migratory potential and invasiveness of cancer cells attribute crucially.in cancer progression. These phenotypes are achieved by precise alteration of invasion-associated genes through local epigenetic modifications which are recognized by a class of proteins termed as chromatin reader. ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), a key component of transcription regulatory network, has been recently shown to be a novel reader of H3.1K36Me2/H4K16Ac marks. Through differential gene expression analysis upon silencing this chromatin reader, we identified a subset of genes involved in cell proliferation and invasion/migration regulated by ZMYND8. Detailed analysis uncovered its anti-proliferative activity through BrdU incorporation, alteration in the expression of proliferation markers and cell cycle regulating genes and cell viability assays. In addition, performing wound healing and invasion/migration assays, its anti-invasive nature is evident. Interestingly, epithelial-mesenchymal transition, a key mechanism of cellular invasion, is regulated by ZMYND8 where we identified its selective enrichment on promoters of CLDN1 / CDH1 genes, rich in H3K36Me2/H4K16Ac marks, leading to their upregulation. Thus, presence of ZMYND8 could be implicated in maintaining the epithelial phenotype of cells. Further, syngeneic mice, injected with ZMYND8-overexpressed invasive breast cancer cells showed reduction in tumor volume and weight. In concert with this, we observed a significant downregulation of ZMYND8 in invasive ductal and lobular breast cancer tissues compared to normal one. Taken together, our study elucidates a novel function of ZMYND8 in regulating EMT and invasion of cancer cells, possibly through its chromatin reader function. ©2017 The Author(s).
Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma
Apr 22, 2017   Blood
Rasche L, Angtuaco E, McDonald JE, Buros A, Stein C,   . . . . . .   , Houlston R, Barlogie B, Davies FE, Morgan GJ, Weinhold N
Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma
Apr 22, 2017
Blood
18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) and diffusion weighted magnetic resonance imaging with background signal suppression (DWIBS) are two powerful functional imaging modalities in the evaluation of the malignant plasma cell (PC) disease multiple myeloma (MM). Preliminary observations have suggested that MM patients with extensive disease according to DWIBS may be reported as being disease-free on FDG-PET ("PET-false-negative"). The aim of this study was to describe the proportion of PET-false-negativity in a representative set of 227 newly diagnosed MM patients with simultaneous assessment of FDG-PET and DWIBS, and to identify tumor-intrinsic features associated with this pattern. We found the incidence of PET-false-negativity to be 11%. Neither tumor-load associated parameters, such as the degree of bone marrow PC infiltration, nor the PC proliferation rate were associated with this subset. However, the gene coding for Hexokinase-2, which catalyzes the first step of glycolysis, was significantly lower expressed in PET false-negative cases (5.3-fold change, P
Dynamics of growth zone patterning in the milkweed bug Oncopeltus fasciatus
Apr 22, 2017   Development (Cambridge, England)
Auman T, Vreede BMI, Weiss A, Hester SD, Williams TA, Nagy LM, Chipman AD
Dynamics of growth zone patterning in the milkweed bug Oncopeltus fasciatus
Apr 22, 2017
Development (Cambridge, England)
We describe the dynamic process of abdominal segment generation in the milkweed bug Oncopeltus fasciatus We present detailed morphological measurements of the growing germband throughout segmentation. Our data are complemented by cell division profiles and expression patterns of key genes, including invected and even-skipped as markers for different stages of segment formation. We describe morphological and mechanistic changes in the growth zone and in nascent segments during generation of individual segments and throughout segmentation, and examine the relative contribution of newly formed versus existing tissue to segment formation. While abdominal segment addition is primarily generated through cell rearrangement of a pool of undifferentiated cells, there is nonetheless proliferation in the posterior. By correlating proliferation with gene expression in the growth zone, we propose a model for the dynamics of the growth zone during segmentation in which the growth zone is functionally subdivided into two separate regions: a posterior region devoted to a slow rate of growth among undifferentiated cells and an anterior region in which segmental differentiation is initiated and proliferation inhibited. © 2017. Published by The Company of Biologists Ltd.
ERK expression and its correlation with STAT1 in esophageal squamous cell carcinoma
Apr 21, 2017   Oncotarget
Wang H, Zhang Y, Yun H, Chen S, Chen Y, Liu Z
ERK expression and its correlation with STAT1 in esophageal squamous cell carcinoma
Apr 21, 2017
Oncotarget
Esophageal squamous cell carcinoma is one of leading causes of cancer-related deaths in Chaoshan region a high-risk region for esophageal cancer. Extracellular regulated protein kinases (ERK) usually play an important role in cell proliferation and differentiation. However, accumulating evidence has shown that the ERK was aberrantly expressed in cancers and correlated with STAT1 depression. The activated ERK downregulates STAT1 expression in ESCC cell lines and U0126 increases expression of STAT1. Our immunohistochemistry result also confirms that the expression of ERK inversely correlated with that of STAT1 in ESCC tumors. In addition, a significantly higher expression of ERK/p-ERK was found in ESCC tissues in comparison with case-matched normal esophageal tissues (p < 0.05). Moreover, the immunohistochemical analysis demonstrated that ERK expression was paralleled with the differentiation and clinical stage. In 74 patients with follow-up data, those with ERKlow tumors survived significantly longer than those with ERKhigh tumors (p = 0.04); patients with ERKlow/STAT1high tumors had the longest survival (p = 0.001). To investigate whether ERK can mediated STAT1 expression in ESCC, we used the MEK plasmid and U0126, a MEK inhibitor, to treat the cell. To further confirm our in-vitro study, we detected the ERK, p-ERK and STAT1 expression in 131 ESCC cases and 22 case-matched normal esophageal tissues adjacent to the tumors specimens. These findings provide pathological evidence that ERK/p-ERK is negatively correlated with STAT1 in ESCC. Our data suggests that inhibition of ERK and/or restoration of STAT1 expression maybe useful therapeutic strategies for ESCC.
Sequential Adaptive Changes in a c-Myc-Driven Model of Hepatocellular Carcinoma
Apr 22, 2017   The Journal Of Biological Chemistry
Dolezal JM, Wang H, Kulkarni S, Jackson L, Lu J, Ranganathan S, Goetzman ES, Bharathi S, Beezhold K, Byersdorfer CA, Prochownik EV
Sequential Adaptive Changes in a c-Myc-Driven Model of Hepatocellular Carcinoma
Apr 22, 2017
The Journal Of Biological Chemistry
Hepatocellular carcinoma (HCC) is a common cancer that frequently over-expresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical and molecular changes accompanying HCC progression, regression and recurrence. These involved altered rates of pyruvate and fatty acid β-oxidation and the likely re-directing of glutamine into biosynthetic rather than energy-generating pathways. Initial tumors also showed reduced mitochondrial mass and differential contributions of electron transport chain Complexes I and II to respiration. The uncoupling of Complex II's electron transport function from its succinate dehydrogenase activity also suggested a mechanism by which Myc generates reactive oxygen species. RNA-Seq studies revealed an orderly progression of transcriptional changes involving pathways pertinent to DNA damage repair, cell cycle progression, insulin-like growth factor signaling, innate immunity and further metabolic re-programming. Only a subset of functions deregulated in initial tumors were similarly deregulated in recurrent tumors thereby indicating that the latter can "normalize" some behaviors to suit their needs. An interactive and freely available software tool was developed to allow continued analyses of these and other transcriptional profiles. Collectively, these studies define the metabolic, biochemical and molecular events accompanying HCC evolution, regression and recurrence in the absence of any potentially confounding therapies. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
In vivo and in vitro study of osteogenic potency of endothelin-1 on bone marrow-derived mesenchymal stem cells
Apr 22, 2017   Experimental Cell Research
Hu LW, Wang X, Jiang XQ, Xu LQ, Pan HY
In vivo and in vitro study of osteogenic potency of endothelin-1 on bone marrow-derived mesenchymal stem cells
Apr 22, 2017
Experimental Cell Research
Bone marrow-derived mesenchymal stem cells (BMSCs) are a major source of osteoblasts and are crucial for bone remolding and repair and thus they are widely used for tissue engineering applications. Tissue engineering in combination with gene therapy is considered as a promising approach in new bone regeneration. Endothelin-1(EDN-1)is produced by vascular endothelial cells which plays an important role during bone development. However, its role in BMSCs remains largely unknown. We established EDN-1 overexpressed BMSCs, proliferation ability and osteogenesis differentiation were detected respectively. Transduced BMSCs were then combined with CPC-scaffold to repair calvarial defects in rats to evaluate the in-vivo osteogenic potential of EDN-1. EDN-1 overexpressed BMSCs showed increased proliferation and significantly increased osteogenesis potential ability than vector transfected control. The in-vivo data also revealed more new bone formation with higher bone mineral density and number of trabeculae in EDN-1 overexpressed BMSCs. These findings have demonstrated the influence of EDN-1 on differentiation potential of BMSCs, which suggest that EDN-1 may be a new promising agent for bone tissue engineering. Copyright © 2017. Published by Elsevier Inc.
Clinicopathologic, Radiologic, and Molecular Study of 23 Combined Hepatocellular-Cholangiocarcinomas with Stem Cell Features, Cholangiolocellular Type
Apr 22, 2017   Human Pathology
Chen J, He J, Deng M, Wu HY, Shi J, Mao L, Sun Q, Tang M, Fan XS, Qiu YD, Huang Q
Clinicopathologic, Radiologic, and Molecular Study of 23 Combined Hepatocellular-Cholangiocarcinomas with Stem Cell Features, Cholangiolocellular Type
Apr 22, 2017
Human Pathology
Cholangiolocellular carcinoma is a type of intrahepatic cholangiocarcinoma (ICC). According to the 2010 World Health Organization classification, this carcinoma is a combined hepatocellular-cholangiocarcinoma with stem cell features, cholangiolocellular type (CHC-SC-CLC). The aim of this study was to compare the clinicopathologic characteristics of CHC-SC-CLC and conventional ICC. Based on the gross and histologic characteristics, we divided consecutive ICC tumors into CHC-SC-CLC (n = 23), mass-forming (MF, n = 57), and non-MF (n = 22) groups. Compared with MF and non-MF groups, the CHC-SC-CLC group featured history of hepatolithiasis or bile duct operation in significantly fewer patients (4.3% versus 14.8% and 86.4%, respectively; P < .001) and was more common in the right lobe (70% versus 47% and 27%; P =.033) but lower frequency of invasive growth or peritumoral Glisson's sheath invasion (PGSI; 61% and 22% versus 77% and 33% and 100% and 86%, respectively; P = .002 and P < .001) and absence of mucous production (0 versus 77% and 96%; P < .001). In CHC-SC-CLCs, the mutation rate of isocitrate dehydrogenase 1 (IDH1) or IDH2 was significantly higher (35%) than in MF (4%) or non-MF (0) ICCs (P < .001). The 1-, 3-, and 5-year post-resection survival rates were also significantly better with CHC-SC-CLCs (93%, 79%, and 52%, respectively) than with MF (72%, 46%, and 40%) or non-MF (61%, 18%, and 0) ICCs (P = .041). Thus, CHC-SC-CLC tumors demonstrated an indolent growth pattern, more frequent IDH1/2 gene mutations, and better prognosis than MF or non-MF ICC tumors. Copyright © 2017. Published by Elsevier Inc.
Absence of myoepithelial cells correlates with invasion and metastasis of Carcinoma ex pleomorphic adenoma
Apr 22, 2017   International Journal Of Oral And Maxillofacial Surgery
Ye P, Gao Y, Wei T, Yu GY, Peng X
Absence of myoepithelial cells correlates with invasion and metastasis of Carcinoma ex pleomorphic adenoma
Apr 22, 2017
International Journal Of Oral And Maxillofacial Surgery
Myoepithelial cells (MECs) are implicated in the development and progression of human salivary gland tumours. Here, we investigate the potential role for MECs in invasion and metastasis of carcinoma ex pleomorphic adenoma (CXPA). Tumour tissues from 40 CXPA patients diagnosed between 1960 and 2014 were obtained. Patient samples were divided into two groups (non-invasive tumours, n=10; and frankly invasive tumours, n=30). Each group was further divided into two subgroups (metastatic tumours and non-metastatic tumours). Immunohistochemistry for MEC markers (α-SMA, CALPONIN, and p63) was performed, and the number and distribution of MECs was quantified. For non-invasive CXPAs, non-metastatic cases (n=8) displayed a significant enrichment in CALPONIN(+) and α-SMA(+) MECs, but not p63(+) MECs, compared with metastatic cases (n=2). Likewise, for frankly invasive CXPAs (n=30), non-metastatic cases showed a significant enrichment for α-SMA(+), CALPONIN(+), and p63(+) MECs compared with metastatic cases (n=15). We demonstrate that non-invasive CXPAs have the potential for metastasis. Furthermore, the tumour capsule may not be the only barrier preventing invasion and metastasis, as a significant reduction in numbers of myoepithelial cells correlates with invasion and metastasis in CXPA patients. Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
eEF2K promotes progression and radioresistance of esophageal squamous cell carcinoma
Apr 22, 2017   Radiotherapy And Oncology : Journal Of The European Society For Therapeutic Radiology And Oncology
Zhu H, Song H, Chen G, Yang X, Liu J,   . . . . . .   , Di X, Cai J, Ma J, Zhang S, Sun X
eEF2K promotes progression and radioresistance of esophageal squamous cell carcinoma
Apr 22, 2017
Radiotherapy And Oncology : Journal Of The European Society For Therapeutic Radiology And Oncology
To investigate the biological function of eEF2K in esophageal squamous cell carcinoma (ESCC). Tissue microarrays containing 100 pairs of ESCC tumor and adjacent normal tissues were completed. Overexpression and knockdown of eEF2K were constructed in ECA-109 and TE-13 ESCC cells. DNA damage, cell viability, migration and invasion, radioresistance, apoptosis and autophagy were determined by immunofluorescence, CCK-8, transwell assay, colony formation assay, flow cytometry and western blot, respectively. Tumor growth and radioresistance were also evaluated using xenograft models created in nude mice. eEF2K expression was higher in ESCC tissues compared with matched non-tumor tissues (P
Overexpression of miR-584-5p inhibits proliferation and induces apoptosis by targeting WW domain-containing E3 ubiquitin protein ligase 1 in gastric cancer
Apr 22, 2017   Journal Of Experimental & Clinical Cancer Research : CR
Li Q, Li Z, Wei S, Wang W, Chen Z,   . . . . . .   , Xu Z, Xia Y, Zhang D, Xu H, Xu Z
Overexpression of miR-584-5p inhibits proliferation and induces apoptosis by targeting WW domain-containing E3 ubiquitin protein ligase 1 in gastric cancer
Apr 22, 2017
Journal Of Experimental & Clinical Cancer Research : CR
MicroRNAs are endogenously expressed, small non-coding RNAs that modulate gene expression by targeting specific mRNAs, resulting in translational repression or mRNA degradation. Although miR-584-5p has been reported to play a vital role in various malignancies, its role and the molecular mechanisms underlying the effects of miR-584-5p in gastric cancer (GC) remain to be clarified. In this study, we investigated the role of miR-584-5p in GC. The expression of miR-584-5p and its specific target gene were determined in human GC specimens and cell lines by microRNA real-time polymerase chain reaction (RT-PCR), quantitative RT-PCR (qRT-PCR) and Western blot. The effects of miR-584-5p depletion or ectopic expression on GC proliferation were evaluated in vitro using CCK-8 proliferation assays, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, colony formation assays and cell-cycle assays and the in vivo effects were investigated using a mouse tumorigenicity model. Cell apoptosis was evaluated by in vitro flow cytometric analysis, cell viability assays and in vivo TUNEL assays. Luciferase reporter assays were employed to identify interactions between miR-584-5p and its specific target gene. A series of in vitro and in vivo gain- and loss-of-function assays revealed that miR-584-5p inhibited GC cell proliferation, while apoptosis was induced. Luciferase reporter assays and Western blot analysis revealed WWP1 to be a direct target of miR-584-5p. The effects of miR-584-5p-mimic were rescued by WWP1 overexpression. In contrast, the effects of the miR-584-5p-inhibitor were impaired by WWP1-shRNA. Furthermore, miR-584-5p expression levels correlated negatively with WWP1 protein expression in GC tissues and GC cell lines. A series of investigations indicated that miR-584-5p promoted senescence and activated the TGFβ signaling pathway by downregulation of WWP1. Taken together, these results suggest that downregulation of miR-584-5p contributes to tumor progression by downregulation of WWP1, thus, highlighting the potential of miR-584-5p as a therapeutic target for human GC.
Cripto-1 acts as a functional marker of cancer stem-like cells and predicts prognosis of the patients in esophageal squamous cell carcinoma
Apr 22, 2017   Molecular Cancer
Liu Q, Cui X, Yu X, Bian BS, Qian F,   . . . . . .   , Zhang X, Zhang P, Wang JM, Cui YH, Bian XW
Cripto-1 acts as a functional marker of cancer stem-like cells and predicts prognosis of the patients in esophageal squamous cell carcinoma
Apr 22, 2017
Molecular Cancer
Esophageal squamous cell carcinoma (ESCC) is highly malignant with highly invasive and metastatic capabilities and poor prognosis. It is believed that the ESCC cancer stem-like cells (ECSLCs) are critical for tumorigenicity, invasion and metastasis of ESCC. However, the properties of ECSLCs vary with different markers used in isolation, so that new and more effective markers of ECSLCs need to be identified. This study aimed to estimate the potentiality of Cripto-1 (CR-1) as an ECSLC surface marker and investigate the clinical significance of CR-1 expression in ESCC. ESCC cells with CR-1 high or CR-1low were obtained by flow cytometry then their self-renewal capability and tumorigenicity were compared by colony and limiting dilution sphere formation analysis in vitro and xenograft in nude mice in vivo, respectively. Knockdown of CR-1 expression in ESCC cells was conducted with short hairpin RNA. Cell migration and invasion were examined by scratch test and matrigel transwell assay, respectively. Metastatic capability of ESCC cells was assayed by a mouse tail vein metastasis model. The levels of CR-1 expression in cancerous and paired adjacent normal tissues were assessed by IHC and qRT-RCR. CR-1high subpopulation of ESCC cells isolated by FACS expressed high level of genes related to stemness and epithelial-mesenchymal transition (EMT), and possessed high capacities of self-renewal, tumorigenesis, invasion and metastasis. Suppression of CR-1 expression significantly reduced the expression of stemness- and EMT-related genes and the capabilities of self-renewal in vitro, tumorigenicity and metastasis in vivo in ESCC cells. In the clinical ESCC specimens, the expression levels of CR-1 in cancerous tissues were positively correlated to TNM stage, invasive depth, and lymph node metastasis. Cox regression analysis indicated that CR-1 was an independent indicator of prognosis. The expression of CR-1 was found overlapping with aldehyde dehydrogenase 1A1 (ALDH1A1), an intracellular marker for ESCLCs, in ESCC cell lines and specimens. CR-1 is a functional and cell surface ECSLC marker, and an independent prognostic indicator as well as a potential therapeutic target for ESCC.
Hepatitis C virus NS4B protein induces epithelial-mesenchymal transition by upregulation of Snail
Apr 22, 2017   Virology Journal
Hu B, Xie S, Hu Y, Chen W, Chen X, Zheng Y, Wu X
Hepatitis C virus NS4B protein induces epithelial-mesenchymal transition by upregulation of Snail
Apr 22, 2017
Virology Journal
Chronic hepatitis C virus (HCV) infection is an important cause of hepatocellular carcinoma (HCC). Epithelial to mesenchymal transition (EMT) is a key process associated with tumor metastasis and poor prognosis. HCV infection, HCV core and NS5A protein could induce EMT process, but the role of NS4B on EMT remains poorly understood. We overexpressed HCV NS4B protein in HepG2 cells or Huh7.5.1 cells infected by HCVcc, the E-cadherin expression, N-cadherin expression and the EMT-associated transcriptional factor Snail were determined. The migration and invasion capabilities of the transfected cells were evaluated using wound-healing assay. Additionally, we used Snail siRNA interference to confirm the relation of HCV NS4B and Snail on EMT promotion. HCV NS4B increased the expression of EMT related markers and promoted cell migration and invasion. Snail knock-down almost completely eliminated the function of NS4B protein in EMT changes and reversed cell migration capacity to lower level. HCV NS4B protein could reduce the expression of Scribble and Hippo signal pathway were subsequently inactivated, resulting in the activation of PI3K/AKT pathway, which may be the reason for the up-regulation of Snail. This study demonstrates that HCV NS4B protein induces EMT progression via the upregulation of Snail in HCC, which may be a novel underlying mechanism for HCV-associated HCC development, invasion and metastasis.
Evaluation of the correlation of vasculogenic mimicry, ALDH1, KAI1 and microvessel density in the prediction of metastasis and prognosis in colorectal carcinoma
Apr 22, 2017   BMC Surgery
Zhu B, Zhou L, Yu L, Wu S, Song W, Gong X, Wang D
Evaluation of the correlation of vasculogenic mimicry, ALDH1, KAI1 and microvessel density in the prediction of metastasis and prognosis in colorectal carcinoma
Apr 22, 2017
BMC Surgery
Metastasis and recurrence are the most common reasons for treatment failure of colorectal carcinoma (CRC). Vasculogenic mimicry (VM, blood supply formation often seen in highly aggressive tumors), Aldehyde dehydrogenase 1 (ALDH1, a biomarker of cancer stem cells), KAI1 (a suppressor gene of tumor metastasis) are all valuable factors for metastasis and prognosis in diverse human cancers. However, the correlation of VM, ALDH1, KAI1 and microvessel density (MVD) in CRC is unclear. In this study, we analyzed the correlations among VM, ALDH1, KAI1 and MVD, as well as their respective correlations with clinicopathological parameters and survival in CRC. The level of VM, ALDH1, KAI1 and MVD in 204 whole tissue samples of CRC were examined by immunhistochemistry. Clinical data was also collected. Levels of VM, ALDH1 and MVD were significantly higher, and levels of KAI1 significantly lower, in CRC tissues than in normal colorectal tissues. Levels of VM, ALDH1 and MVD were positively associated with invasion of depth, lymph node metastasis (LNM), distant metastasis and tumor-node-metastasis (TNM) stages, and negatively with patients' overall survival (OS). Levels of KAI1 was negatively correlated with invasion of depth, LNM, distant metastasis and TNM stages, and the KAI1 positive expression subgroup had significantly longer OS than did the KAI1- subgroup. In multivariate analysis, high levels of VM, ALDH1 and KAI1, as well as TNM stages were independently correlated with lower OS in patients with CRC. VM, MVD and the expression of ALDH1 and KAI1 may represent promising metastatic and prognostic biomarkers, as well as potential therapeutic targets for CRC.
Structures and bioactivities of seven flavonoids from Osmanthus fragrans 'Jinqiu' essential oil extraction residues
Apr 22, 2017   Natural Product Research
Zhou JL, Fang XY, Wang JQ, Zhao LG, Li Y, Tang F, Yue YD
Structures and bioactivities of seven flavonoids from Osmanthus fragrans 'Jinqiu' essential oil extraction residues
Apr 22, 2017
Natural Product Research
Osmanthus fragrans are well-known for their fragrance, but it is wasteful if to discard O. fragrans flower after extracting their essential oils. In this paper, we found that O. fragrans flower residues were rich in flavonoids. Six flavonoids and one phenylethanoid glycoside were isolated from the ethanol extract of O. fragrans flower residues, identified as quercetin (1), rutin (2), verbascoside (3), genistin (4), kaempferol (5), isorhamnetin (6) and naringin (7). In bioactivity study, kaempferol (IC50 = 1.43 μg/mL) showed the best anti-inflammatory activity. Isorhamnetin, quercetin, kaempferol, verbascoside and rutin (the values of IC50 were 18.30, 11.05, 16.88, 20.21 and 22.76 μg/mL, respectively) showed excellent DPPH free radical scavenging activity. Verbascoside performed relatively well at inhibiting the growth of both CT26 colonic carcinoma cells (IC50 = 46.87 μg/mL) and HepG2 hepatocarcinoma cells (IC50 = 30.58 μg/mL). In addition, quercetin and kaempferol showed strong anti-proliferation activity against HepG2 cells.
Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular Injury
Apr 22, 2017   The American Journal Of Pathology
Bhatwadekar AD, Beli E, Yanpeng D, Chen J, Luo Q, Alex A, Caballero S, Dominguez JM, Salazar TE, Busik JV, Segal MS, Grant MB
Conditional Deletion of Bmal1 Accentuates Microvascular and Macrovascular Injury
Apr 22, 2017
The American Journal Of Pathology
The brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1 constitutes a major transcriptional regulator of the circadian clock. Here, we explored the impact of conditional deletion of Bmal1 in endothelium and hematopoietic cells in murine models of microvascular and macrovascular injury. We used two models of Bmal1fx/fx;Tek-Cre mice, a retinal ischemia/reperfusion model and a neointimal hyperplasia model of the femoral artery. Eyes were enumerated for acellular capillaries and were stained for oxidative damage markers using nitrotyrosine immunohistochemistry. LSK (lineage-negative, spinocerebellar ataxia type 1 protein homolog-positive, proto-oncogene c-Kit-positive) cells were quantified and proliferation assessed. Hematopoiesis is influenced by innervation to the bone marrow, which we assessed using IHC analysis. The number of acellular capillaries increased threefold, and nitrotyrosine staining increased 1.5-fold, in the retinas of Bmal1fx/fx;Tek-Cre mice. The number of LSK cells from the Bmal1fx/fx;Tek-Cre mice decreased by 1.5-fold and was accompanied by a profound decrease in proliferative potential. Bmal1fx/fx;Tek-Cre mice also exhibited evidence of bone marrow denervation, demonstrating a loss of neurofilament-200 staining. Injured femoral arteries showed a 20% increase in neointimal hyperplasia compared with similarly injured wild-type controls. Our study highlights the importance of the circadian clock in maintaining vascular homeostasis and demonstrates that specific deletion of BMAL1 in endothelial and hematopoietic cells results in phenotypic features similar to those of diabetes. Copyright © 2017. Published by Elsevier Inc.

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