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Cancer Biology
Transcriptional response profiles of paired tumor-normal samples offer novel perspectives in pan-cancer analysis
May 10, 2017   Oncotarget
Hu S, Yuan H, Li Z, Zhang J, Wu J, Chen Y, Shi Q, Ren W, Shao N, Ying X
Transcriptional response profiles of paired tumor-normal samples offer novel perspectives in pan-cancer analysis
May 10, 2017
Oncotarget
Both tumor and adjacent normal tissues are valuable in cancer research. Transcriptional response profiles represent the changes of gene expression levels between paired tumor and adjacent normal tissues. In this study, we performed a pan-cancer analysis based on the transcriptional response profiles from 633 samples across 13 cancer types. We obtained two interesting results. Using consensus clustering method, we characterized ten clusters with distinct transcriptional response patterns and enriched pathways. Notably, head and neck squamous cell carcinoma was divided in two subtypes, enriched in cell cycle-related pathways and cell adhesion-related pathways respectively. The other interesting result is that we identified 92 potential pan-cancer genes that were consistently upregulated across multiple cancer types. Knockdown of FAM64A or TROAP inhibited the growth of cancer cells, suggesting that these genes may promote tumor development and are worthy of further validations. Our results suggest that transcriptional response profiles of paired tumor-normal tissues can provide novel perspectives in pan-cancer analysis.
[Overexpressed miRNA-134b inhibits proliferation and invasion of CD133+ U87 glioma stem cells]
May 15, 2017   Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal Of Cellular And Molecular Immunology
Liu Y, Zhang B, Wen C, Wen G, Zhou G, Zhang J, He H, Wang N, Li W
[Overexpressed miRNA-134b inhibits proliferation and invasion of CD133+ U87 glioma stem cells]
May 15, 2017
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal Of Cellular And Molecular Immunology
Objective To investigate the role of microRNA-134b (miR-134b) in the tumorigenesis of glioma stem cells (GSCs) and the possible molecular mechanism. Methods Real-time quantitative PCR (qRT-PCR) was used to evalate the expression of miR-134b in CD133+ and CD133- U87 GSCs. A lentiviral vector overexpressing miR-134b in U87 GSCs was constructed, and the effect of miR-134b overexpression on matrix metalloproteinase-2 (MMP-2), MMP-9 and MMP-12 expressions at both mRNA and protein levels were detected by qRT-PCR and Western blotting, respectively. TranswellTM assay was performed to determine the effect of miR-134b overexpression on GSCs invasion ability. Tumor xenograft models in nude mice were established to evaluate the effect of miR-134b overexpression on tumorgenesis in vivo. Results The qRT-PCR showed that, compared with CD133- cells, miR-134b was significantly down-regulated in CD133+ cells. Cell line over-expressing miR-134b was successfully established, and miR-134b was up-regulated significantly compared with empty vector control. Overexpression of miR-134b remarkably inhibited the invasion of U87 GSCs and the expression of MMP-12. However, overexpression of miR-134b did not affect MMP-2 and MMP-9 expressions. miR-134b also suppressed U87 GSCs xenograft growth in vivo. Tumor volume in tumor xenograft model group was significantly lower than that in control group, and tumor weight decreased by 42% in the former group. Conclusion Overexpression of miR-134b inhibits the growth and invasion of CD133+ GSCs.
Chemokine-like factor-like MARVEL transmembrane domain-containing 3 expression is associated with a favorable prognosis in esophageal squamous cell carcinoma
May 19, 2017   Oncology Letters
Han T, Shu T, Dong S, Li P, Li W, Liu D, Qi R, Zhang S, Zhang L
Chemokine-like factor-like MARVEL transmembrane domain-containing 3 expression is associated with a favorable prognosis in esophageal squamous cell carcinoma
May 19, 2017
Oncology Letters
Decreased expression of human chemokine-like factor-like MARVEL transmembrane domain-containing 3 (CMTM3) has been identified in a number of human tumors and tumor cell lines, including gastric and testicular cancer, and PC3, CAL27 and Tca-83 cell lines. However, the association between CMTM3 expression and the clinicopathological features and prognosis of esophageal squamous cell carcinoma (ESCC) patients remains unclear. The aim of the present study was to investigate the correlation between CMTM3 expression and clinicopathological parameters and prognosis in ESCC. CMTM3 mRNA and protein expression was analyzed in ESCC and paired non-tumor tissues by quantitative real-time polymerase chain reaction, western blotting and immunohistochemical analysis. The Kaplan-Meier method was used to plot survival curves and the Cox proportional hazards regression model was also used for univariate and multivariate survival analysis. The results revealed that CMTM3 mRNA and protein expression levels were lower in 82.5% (30/40) and 75% (30/40) of ESCC tissues, respectively, when compared with matched non-tumor tissues. Statistical analysis demonstrated that CMTM3 expression was significantly correlated with lymph node metastasis (P=0.002) and clinical stage (P
Potential role of long non-coding RNA ANRIL in pediatric medulloblastoma through promotion on proliferation and migration by targeting miR-323
May 17, 2017   Journal Of Cellular Biochemistry
Zhang H, Wang X, Chen X
Potential role of long non-coding RNA ANRIL in pediatric medulloblastoma through promotion on proliferation and migration by targeting miR-323
May 17, 2017
Journal Of Cellular Biochemistry
Medulloblastoma (MB) is a common primary tumor of the central nervous system diagnosed in pediatric patients. Survivors of MB are frequently accompanied by severe side effects, thus it is urgent to explore novel therapeutic target. First of all, the level of antisense non-coding RNA in the INK4 locus (ANRIL) in normal cerebellum and DAOY cells were evaluated. Then, the effect of ANRIL on DAOY cell proliferation, migration and apoptosis were tested. Then, qRT-PCR was performed to explore whether ANRIL acted as a sponge of miR-323. The effects of miR-323 inhibition on ANRIL silence-induced alterations of cell proliferation, migration and apoptosis were estimated. Predicted by TargetScan, the possible target gene of miR-323 was screened, followed by validation with luciferase assay. The abnormally expressed BRI3 on cell proliferation, migration, apoptosis and signaling pathways were all evaluated. ANRIL was up-regulated in MB and its silence significantly lowered cell viability and migration but promoted cell apoptosis. ANRIL acted as a sponge of miR-323 and its silence functioned through up-regulating miR-323. BRI3 and CDK6 were target genes of miR-323 and the effect of BRI3 on DAOY cells was the same as ANRIL. Moreover, ANRIL suppression could reduce phosphorylated levels of p38 MAPK, extracellular signal-regulated kinase and AKT, and inhibit Wnt signaling pathway through positively regulating BRI3. ANRIL inhibition repressed cell proliferation and migration but promoted cell apoptosis through miR-323-mediated regulation of BRI3, which could activate p38 MAPK, ERK and AKT as well as Wnt signaling pathway. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Discovery of nitrate-CPK-NLP signalling in central nutrient-growth networks
May 10, 2017   Nature Add nature.com free-link Cancel
Liu KH, Niu Y, Konishi M, Wu Y, Du H,   . . . . . .   , Ishida T, Zhang C, Shokat K, Yanagisawa S, Sheen J
Discovery of nitrate-CPK-NLP signalling in central nutrient-growth networks
May 10, 2017
Nature
Nutrient signalling integrates and coordinates gene expression, metabolism and growth. However, its primary molecular mechanisms remain incompletely understood in plants and animals. Here we report unique Ca2+ signalling triggered by nitrate with live imaging of an ultrasensitive biosensor in Arabidopsis leaves and roots. A nitrate-sensitized and targeted functional genomic screen identifies subgroup III Ca2+-sensor protein kinases (CPKs) as master regulators that orchestrate primary nitrate responses. A chemical switch with the engineered mutant CPK10(M141G) circumvents embryo lethality and enables conditional analyses of cpk10 cpk30 cpk32 triple mutants to define comprehensive nitrate-associated regulatory and developmental programs. Nitrate-coupled CPK signalling phosphorylates conserved NIN-LIKE PROTEIN (NLP) transcription factors to specify the reprogramming of gene sets for downstream transcription factors, transporters, nitrogen assimilation, carbon/nitrogen metabolism, redox, signalling, hormones and proliferation. Conditional cpk10 cpk30 cpk32 and nlp7 mutants similarly impair nitrate-stimulated system-wide shoot growth and root establishment. The nutrient-coupled Ca2+ signalling network integrates transcriptome and cellular metabolism with shoot-root coordination and developmental plasticity in shaping organ biomass and architecture.
Common pitfalls in preclinical cancer target validation
May 19, 2017   Nature Reviews. Cancer
Kaelin WG
Common pitfalls in preclinical cancer target validation
May 19, 2017
Nature Reviews. Cancer
An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.
Selective Dopamine Receptor 4 Activation Mediates the Hippocampal Neuronal Calcium Response via IP3 and Ryanodine Receptors
May 16, 2017   Brain Research
Wang YL, Wang JG, Guo FL, Gao XH, Zhao DD, Zhang L, Wang JZ, Lu CB
Selective Dopamine Receptor 4 Activation Mediates the Hippocampal Neuronal Calcium Response via IP3 and Ryanodine Receptors
May 16, 2017
Brain Research
Intracellular calcium is a key factor in most cellular processes, including cell growth, differentiation, proliferation and neurotransmitter release. Dopamine (DA) mediates synaptic transmission by regulating the intracellular calcium content. It is not clear, however, which specific subunit of the DA receptor contributes to DA modulation of intracellular calcium content changes. Through the traditional technique of Fura-2 calcium imaging, this study demonstrated that the DA can induce transient calcium in cultured hippocampal neurons and that this response can be mimicked by a selective dopamine receptor 4 (DR4) agonist PD168077 (PD). PD-induced calcium transience can be blocked by a calcium chelator, such as BAPTA-AM, or by pre-treatment of neurons with thapsigargin, a IP3 receptor antagonist, or a micromolar concentration of ryanodine, a ryanodine receptor (RyR) antagonist. However PD-induced calcium transience cannot be blocked by pre-treatment of neurons with a free-calcium medium or a cocktail of NMDA receptor, L-type calcium channel and alpha7 nicotinic acetylcholine receptor blockers. These results indicate that the calcium response induced by DR4 activation is mainly through activation of IP3 receptor in internal stores, which is likely to contribute to the DA modulation of synaptic transmission and cognitive function. Copyright © 2017. Published by Elsevier B.V.
MicroRNA-1299 is a negative regulator of STAT3 in colon cancer
May 12, 2017   Oncology Reports
Wang Y, Lu Z, Wang N, Zhang M, Zeng X, Zhao W
MicroRNA-1299 is a negative regulator of STAT3 in colon cancer
May 12, 2017
Oncology Reports
Signal transducers and activators of transcription (STAT) is a family of transcription factors which regulate cell proliferation, differentiation, apoptosis, metastasis, immune and inflammatory responses, and angiogenesis. STAT3 is a latent cytoplasmic transcription factor that belongs to STATs. STAT3 has been reported be regulates genes involved with cellular growth, proliferation and metastasis. Worldwide, colon cancer is one of the leading causes of cancer-related deaths. Cumulative evidence has established that STAT3 is essential for colon cancer progression to advanced malignancy. In our study, we showed that microRNA-1299 (miR-1299) was closely related to the TNM stage of colon cancer, and that the expression of miR-1299 was negatively correlated with the expression of STAT3 in colon cancer which means that miR-1299 can be a negative regulator of STAT3 in colon cancer. A total of 60 cases of different grades of colon samples were used to detect the expression of miR-1299. Results showed that miR-1299 was significantly lower in high-grade colons both in mRNA and protein levels. Furthermore, Overall survival (OS) in patients with low miR-1299 is shorter than 25.6 months, as compared with an OS of 28.4 months in patients with high level of miR-1299. We also confirmed that the overexpression of miR-1299 can not only downregulate the STAT3 pathway, but also inhibited colon cancer cell growth. Our findings could provide new insights into the molecular therapeutic of colon cancer.
Differential Proteomics Reveals the Potential Injury Mechanism Induced by Heavy Ion Radiation in Mice Ovaries
May 12, 2017   Biomedical And Environmental Sciences : BES
He YX, Zhang H, Li HY, Zhang Y, Jia QP, Li ZS, Zhao XX
Differential Proteomics Reveals the Potential Injury Mechanism Induced by Heavy Ion Radiation in Mice Ovaries
May 12, 2017
Biomedical And Environmental Sciences : BES
In the present study, we used a proteomics approach based on a two-dimensional electrophoresis (2-DE) reference map to investigate protein expression in the ovarian tissues of pubertal Swiss-Webster mice subjected to carbon ion radiation (CIR). Among the identified proteins, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is associated with the cell cycle[1] and that it influences proliferation in ovarian tissues. We analyzed the expression of UCH-L1 and the proliferation marker proliferation cell nuclear antigen (PCNA) following CIR using immunoblotting and immunofluorescence. The proteomics and biochemical results provide insight into the underlying mechanisms of CIR toxicity in ovarian tissues. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.
Carbohydrate antigen 125 and carcinoembryonic antigen in the differentiation of tuberculous peritonitis and peritonitis carcinomatosa
May 11, 2017   Oncotarget
Tong H, Tai Y, Ye C, Wu H, Zhang LH, Gao JH, Yan ZP, Huang ZY, Tang CW
Carbohydrate antigen 125 and carcinoembryonic antigen in the differentiation of tuberculous peritonitis and peritonitis carcinomatosa
May 11, 2017
Oncotarget
Tumor markers could increase in both tuberculous peritonitis and peritonitis carcinomatosa, confusing the differentiation of these diseases. This study aimed to better understand the extent of elevation and diagnostic efficacies of carbohydrate antigen 125 (CA 125), carcinoembryonic antigen (CEA) and combinative use of them in tuberculous peritonitis and peritonitis carcinomatosa. Of 2998 patients reviewed, 101, 120 and 71 patients were assigned to TBP group (tuberculous peritonitis), non-OCA group (non-ovarian carcinoma-related peritonitis carcinomatosa) and OCA group (ovarian carcinoma-related peritonitis carcinomatosa), respectively. The composite index was calculated by CA 125 multiplying CEA. Receiver operator characteristic curves for CA 125, CEA and composite index were acquired. As a result, CA 125 value in OCA group was higher than other two groups (serum CA 125: P < 0.001; ascites CA 125: P < 0.001). On the other hand, non-OCA group had the highest CEA value among three groups (serum CEA: P < 0.001; ascites CEA: P < 0.001). Area under curves of serum/ascites composite index and serum/ascites CEA were larger than those of serum/ascites CA 125. Furthermore, ascites and serum composite index displayed the best sensitivity (0.907) and specificity (0.989), respectively. In conclusion, CA 125 increases in tuberculous peritonitis and non-ovarian carcinoma-related peritonitis carcinomatosa, but it elevates more in ovarian carcinoma-related peritonitis carcinomatosa. CEA is found to increase more significantly in non-ovarian carcinoma-related peritonitis carcinomatosa. CEA and composite index are helpful in distinguishing peritonitis carcinomatosa from tuberculous peritonitis, but composite index is slightly superior to CEA in the differential diagnosis.
The soy-derived peptide Vglycin inhibits the growth of colon cancer cells in vitro and in vivo
May 11, 2017   Experimental Biology And Medicine (Maywood, N.J.)
Gao C, Sun R, Xie YR, Jiang AL, Lin M, Li M, Chen ZW, Zhang P, Jin H, Feng JP
The soy-derived peptide Vglycin inhibits the growth of colon cancer cells in vitro and in vivo
May 11, 2017
Experimental Biology And Medicine (Maywood, N.J.)
Vglycin, a novel natural polypeptide isolated from pea seeds, possesses antidiabetic properties. Our previous studies have shown that Vglycin can induce the differentiation of human colon adenocarcinoma cells. We aimed to determine the anticancer activity of Vglycin against colon cancer cells and to elucidate related apoptosis-inducing mechanisms. Treatment with purified Vglycin significantly reduced growth, viability, and colony formation of CT-26, SW480, and NCL-H716 colon cancer cells in a dose-dependent manner while down-regulating the expression of proliferating cell nuclear antigen. Mouse xenograft studies showed a 38% inhibition of colon cancer growth in mice treated with Vglycin (20 mg/kg/day) at day 21. Furthermore, the potential mechanisms involved in Vglycin-induced cell apoptosis were examined using cell cycle studies, ultrastructural examination, as well as apoptosis-associated pathway analysis. The results showed that Vglycin significantly promoted apoptosis and G1/S phase cell cycle arrest. As revealed by Western blot, the expression of CDK2 and Cyclin D1 was down-regulated in all three Vglycin-treated colon cancer cells, indicating that the CDK2/Cyclin D1 cell cycle pathway involved in the initiation and progression of colon cancer. Moreover, the inhibition of Vglycin-induced cell proliferation in colon cancer cells was accompanied by alteration of the expression levels of the apoptosis-related proteins Bax, Bcl-2 and Mcl-1, and an increase of caspase-3 activity. Together, our results suggest that Vglycin may be another plant-derived peptide that suppresses colon cancer, supporting the continued investigation of Vglycin as therapeutic agent for colon cancer. Impact statement The antidiabetic properties and the capability of inducing differentiation of human colon adenocarcinoma cells of Vglycin have been reported in our previous studies. However, the anticancer potential of Vglycin on colon cancer cells and its possible related mechanisms were still unknown. In this study, we found that Vglycin could reduce growth, viability, and colony formation or colony size of CT-26, SW480, and NCL-H716 colon cancer cells. Moreover, Vglycin decreased tumor volume by 38% in xenograft mice transplanted with CT-26 cells. The mechanisms of these phenomena may be due to the down-regulated CDK2 and Cyclin D1, G1/S phase cell cycle arrest, and the dysregulated expression of Bax, Bcl-2, and Mcl-1. The findings highlight the anticancer potential of Vglycin against colon cancer cells, and suggest Vglycin may be another colon cancer potential suppressive component of plant-derived peptides.
Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver
May 12, 2017   Science (New York, N.Y.)
Minutti CM, Jackson-Jones LH, García-Fojeda B, Knipper JA, Sutherland TE,   . . . . . .   , Stamme C, Chroneos ZC, Zaiss DM, Casals C, Allen JE
Local amplifiers of IL-4Rα-mediated macrophage activation promote repair in lung and liver
May 12, 2017
Science (New York, N.Y.)
The type 2 immune response controls helminth infection and maintains tissue homeostasis but can lead to allergy and fibrosis if not adequately regulated. We have discovered local tissue-specific amplifiers of type-2 mediated-macrophage activation. In the lung, surfactant protein A (SP-A) enhanced IL-4-dependent macrophage proliferation and activation, accelerating parasite clearance and reducing pulmonary injury following infection with a lung-migrating helminth. In the peritoneal cavity and liver, C1q enhancement of type 2 macrophage activation was required for liver repair following bacterial infection, but resulted in fibrosis following peritoneal dialysis. IL-4 drives production of these structurally related defense collagens, SP-A and C1q, and the expression of their receptor, myosin 18A. These findings reveal the existence within different tissues of an amplification system needed for local type 2 responses. Copyright © 2017, American Association for the Advancement of Science.
Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells
May 12, 2017   Science (New York, N.Y.)
Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD,   . . . . . .   , Gagliani N, Craft JE, Flavell RA, Ghosh S, Rothlin CV
Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells
May 12, 2017
Science (New York, N.Y.)
Tissue repair is a subset of a broad repertoire of IL-4/IL-13-dependent host responses during helminth infection. Here, we show that IL-4/IL-13 alone were not sufficient, but IL-4/IL-13 together with apoptotic cells induced the tissue repair program in macrophages. Genetic ablation of sensors of apoptotic cells impaired the proliferation of tissue-resident macrophages and the induction of anti-inflammatory/tissue repair genes in the lung following helminth infection or in the gut following induction of colitis. In contrast, the recognition of apoptotic cells was dispensable for cytokine-dependent induction of pattern recognition receptor, cell adhesion or chemotaxis genes in macrophages. Detection of apoptotic cells can therefore spatially compartmentalize or prevent premature or ectopic activity of pleiotropic, soluble cytokines, such as IL-4/IL-13. Copyright © 2017, American Association for the Advancement of Science.
Lineage-dependent spatial and functional organization of the mammalian enteric nervous system
May 19, 2017   Science (New York, N.Y.)
Lasrado R, Boesmans W, Kleinjung J, Pin C, Bell D, Bhaw L, McCallum S, Zong H, Luo L, Clevers H, Vanden Berghe P, Pachnis V
Lineage-dependent spatial and functional organization of the mammalian enteric nervous system
May 19, 2017
Science (New York, N.Y.)
The enteric nervous system (ENS) is essential for digestive function and gut homeostasis. Here we show that the amorphous neuroglia networks of the mouse ENS are composed of overlapping clonal units founded by postmigratory neural crest-derived progenitors. The spatial configuration of ENS clones depends on proliferation-driven local interactions of ENS progenitors with lineally unrelated neuroectodermal cells, the ordered colonization of the serosa-mucosa axis by clonal descendants, and gut expansion. Single-cell transcriptomics and mutagenesis analysis delineated dynamic molecular states of ENS progenitors and identified RET as a regulator of neurogenic commitment. Clonally related enteric neurons exhibit synchronous activity in response to network stimulation. Thus, lineage relationships underpin the organization of the peripheral nervous system. Copyright © 2017, American Association for the Advancement of Science.
The Fragment HMGA2-sh-3p20 from HMGA2 mRNA 3'UTR Promotes the Growth of Hepatoma Cells by Upregulating HMGA2
May 19, 2017   Scientific Reports
Wang Y, Chen F, Yang Z, Zhao M, Zhang S, Gao Y, Feng J, Yang G, Zhang W, Ye L, Zhang X
The Fragment HMGA2-sh-3p20 from HMGA2 mRNA 3'UTR Promotes the Growth of Hepatoma Cells by Upregulating HMGA2
May 19, 2017
Scientific Reports
High mobility group A2 (HMGA2) plays a crucial role in the development of cancer. However, the mechanism by which HMGA2 promotes the growth of hepatocellular carcinoma (HCC) remains unclear. Here, we explore the hypothesis that HMGA2 may enhance the growth of hepatoma cells through a fragment based on the secondary structure of HMGA2 mRNA 3'-untranslated region (3'UTR). Bioinformatics analysis showed that HMGA2 mRNA displayed a hairpin structure within its 3'UTR, termed HMGA2-sh. Mechanistically, RNA immunoprecipitation assays showed that the microprocessor Drosha or DGCR8 interacted with HMGA2 mRNA in hepatoma cells. Then, Dicer contributes to the generation of the fragment HMGA2-sh-3p20 from the HMGA2-sh. HMGA2-sh-3p20 was screened by PCR analysis. Interestingly, HMGA2-sh-3p20 increased the expression of HMGA2 through antagonizing the tristetraprolin (TTP)-mediated degradation of HMGA2. HMGA2-sh-3p20 inhibited the expression of PTEN by targeting the 3'UTR of PTEN mRNA. In addition, the overexpression of PTEN could downregulate HMGA2 expression. Significantly, we documented the ability of HMGA2-sh-3p20 to promote the growth of hepatoma cells in vitro and in vivo. Thus, we conclude that the fragment HMGA2-sh-3p20 from HMGA2 mRNA 3'UTR promotes the growth of hepatoma cells by upregulating HMGA2. Our finding provides new insights into the mechanism by which HMGA2 enhances hepatocarcinogenesis.
Activated hepatic stellate cells secrete periostin to induce stem cell-like phenotype of residual hepatocellular carcinoma cells after heat treatment
May 20, 2017   Scientific Reports
Zhang R, Yao RR, Li JH, Dong G, Ma M, Zheng QD, Gao DM, Cui JF, Ren ZG, Chen RX
Activated hepatic stellate cells secrete periostin to induce stem cell-like phenotype of residual hepatocellular carcinoma cells after heat treatment
May 20, 2017
Scientific Reports
Some evidences show that residual tumor after thermal ablation will progress rapidly. However, its mechanisms remain unclear. Here, we assessed whether activated HSCs could regulate stem cell-like property of residual tumor after incomplete thermal ablation to promote tumor progression. Human HCC cell lines were exposed to sublethal heat treatment to simulate the peripheral zone of thermal ablation. After residual HCC cells were cultured with conditional medium (CM) from activated HSCs, parameters of the stem cell-like phenotypes were analyzed. Nude mice bearing heat-exposed residual HCC cells and HSCs were subjected to metformin treatment to thwarter tumor progression. CM from activated primary HSCs or LX-2 cells significantly induced the stem cell-like phenotypes of residual HCC cells after heat treatment. These effects were significantly abrogated by neutralizing periostin (POSTN) in the CM. POSTN regulated the stemness of heat-exposed residual HCC cells via activation of integrin β1/AKT/GSK-3β/β-catenin/TCF4/Nanog signaling pathway. Metformin significantly inhibited in vivo progression of heat-exposed residual HCC via suppressing POSTN secretion and decreasing cancer stem cell marker expression. Our data propose a new mechanism of activated HSCs promoting the stemness traits of residual HCC cells after incomplete thermal ablation and suggest metformin as a potential drug to reverse this process.
MUG-Mel2, a novel highly pigmented and well characterized NRAS mutated human melanoma cell line
May 19, 2017   Scientific Reports
Rinner B, Gandolfi G, Meditz K, Frisch MT, Wagner K,   . . . . . .   , Lohberger B, Heitzer E, Ghaffari-Tabrizi-Wizsy N, Zweytick D, Zalaudek I
MUG-Mel2, a novel highly pigmented and well characterized NRAS mutated human melanoma cell line
May 19, 2017
Scientific Reports
NRAS mutation in melanoma has been associated with aggressive tumor biology and poor prognosis. Although targeted therapy has been tested for NRAS mutated melanoma, response rates still appear much weaker, than in BRAF mutated melanoma. While plenty of cell lines exist, however, only few melanogenic cell lines retain their in vivo characteristics. In this work we present an intensively pigmented and well-characterized cell line derived from a highly aggressive NRAS mutated cutaneous melanoma, named MUG-Mel2. We present the clinical course, unique morphology, angiogenic properties, growth characteristics using in vivo experiments and 3D cell culture, and results of the exome gene sequencing of an intensively pigmented melanogenic cell line MUG-Mel2, derived from a cutaneous metastasis of an aggressive NRAS p. Q61R mutated melanoma. Amongst several genetic alterations, mutations in GRIN2A, CREBP, PIK3C2G, ATM, and ATR were present. These mutations, known to reinforce DNA repair problems in melanoma, might serve as potential treatment targets. The aggressive and fast growing behavior in animal models and the obtained phenotype in 3D culture reveal a perfect model for research in the field of NRAS mutated melanoma.
Involvement of FAK-ERK2 signaling pathway in CKAP2-induced proliferation and motility in cervical carcinoma cell lines
May 19, 2017   Scientific Reports
Guo QS, Song Y, Hua KQ, Gao SJ
Involvement of FAK-ERK2 signaling pathway in CKAP2-induced proliferation and motility in cervical carcinoma cell lines
May 19, 2017
Scientific Reports
Cervical carcinoma is the fourth most common cause of death in woman, caused by human papillomavirus (HPV) infections and arising from the cervix. Cytoskeleton-associated protein 2 (CKAP2), also known as tumor-associated microtubule-associated protein, has been linked to tumorigenic effects. In the present study, we screened CKAP2 as a new candidate gene which promotes development of cervical carcinoma, in two independent datasets (TCGA and GSE27678). Results showed that CKAP2 expression was significantly up-regulated in cervical cancerous tissues compared with normal counterparts. Gene set enrichment analysis (GSEA) showed that metastasis, cell cycle and FAK pathways were related with elevated CKAP2 expression. Knockdown of CKAP2 expression significantly inhibited cell proliferation, migration and invasion both in HeLa and C-33A cells. And depletion of CKAP2 down-regulated the expression of metastasis and cell cycle related proteins as well as the phosphorylation of ERK2 (p-ERK2), except E-cadherin. In vivo experiment revealed that knockdown of CKAP2 inhibited C-33A cells proliferation. However, FAK inhibitor PF-562271 and ERK2 inhibitor VX-11e treatment significantly inhibited CKAP2 overexpression-induced cell proliferation, migration and invasion in SiHa cells. In conclusion, our study suggests that CKAP2 acts as a functional oncogene in cervical carcinoma development and may exert its function by targeting FAK-ERK2 signaling pathway.
Lactic acid bacteria-specific induction of CD4+Foxp3+T cells ameliorates shrimp tropomyosin-induced allergic response in mice via suppression of mTOR signaling
May 17, 2017   Scientific Reports
Fu L, Peng J, Zhao S, Zhang Y, Su X, Wang Y
Lactic acid bacteria-specific induction of CD4+Foxp3+T cells ameliorates shrimp tropomyosin-induced allergic response in mice via suppression of mTOR signaling
May 17, 2017
Scientific Reports
The beneficial effects of probiotics have been described in allergic sensitization and diseases; however, many questions remain unanswered, such as characteristics of the most effective strains in modulation of allergic responses and how orally administered probiotics affect the systemic immune system. In the present work, oral administration of five lactic acid bacteria strains showed variable effects on protection against the allergic reaction in a mouse model of food allergy to shrimp tropomyosin (ST). The most effective anti-allergic strain, Bacillus coagulans 09.712 (Bc), greatly improved epithelial barrier function and increased lymphocytes proliferation. Moreover, Bc suppresses ST sensitization by altering Th1/Th2/Treg balance as a result of strong induction of CD4+Foxp3+Tregs in combination with IL-10 producing. Bc-specific induction of CD4+Foxp3+ Tregs also suppresses Th17 pro-inflammatory response in this mouse model. Finally, the intake of Bc suppresses mTOR activation and thus the phosphorylation of downstream factors. Inhibition of mTOR signaling by Bc further results in FOXP3 up-regulation and GATA-3 down-regulation, which, in turn, facilitate to control Th2-predominant and Th17 pro-inflammatory responses caused by ST. Our work provides further characterization of the anti-allergic effects of probiotic LAB strains, and identifies new targets for preventive and curative treatment of food allergies.
PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness
May 19, 2017   Scientific Reports
Chang K, Qu Y, Dai B, Zhao JY, Gan H, Shi G, Zhu Y, Shen Y, Zhu Y, Zhang H, Ye D
PD-L1 expression in Xp11.2 translocation renal cell carcinoma: Indicator of tumor aggressiveness
May 19, 2017
Scientific Reports
Programmed death ligand-1 (PD-L1), a promising antitumor target, has proven clinical value against many malignancies. However, the PD-L1 content of Xp11.2 translocation renal cell carcinoma (Xp11.2 RCC) and its correlation with clinical outcomes remain unclear. This study aimed to investigate PD-L1 expression in Xp11.2 RCC and to assess its prognostic value. Formalin-fixed paraffin-embedded specimens from 36 adult patients that were histologically confirmed (by fluorescence in situ hybridization) were subjected to immunohistochemical analysis. Of the 36 Xp11.2 RCC patients, 9 (25.0%) had tumors with positive PD-L1 expression and 27 (75.0%) had tumors with negative PD-L1 expression. Positive PD-L1 expression correlated with advanced tumor stage (P = 0.001), regional lymph node metastasis (P 
Protein kinase C inhibitor chelerythrine selectively inhibits proliferation of triple-negative breast cancer cells
May 18, 2017   Scientific Reports
Lin W, Huang J, Yuan Z, Feng S, Xie Y, Ma W
Protein kinase C inhibitor chelerythrine selectively inhibits proliferation of triple-negative breast cancer cells
May 18, 2017
Scientific Reports
Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking targeted therapy currently. Recent studies imply that protein kinase C may play important roles in TNBC development and could be a specific target. In this study, we evaluated the anti-proliferative activity of PKC inhibitor chelerythrine on a panel of breast cancer cell lines. Chelerythrine selectively inhibited the growth of TNBC cell lines compared to non-TNBC cell lines as demonstrated by in vitro cell proliferation assay and colony formation assay, as well as evidenced by in vivo xenograft assay. The selective anti-proliferative effect of chelerythrine was associated with induction of apoptosis in TNBC cell lines. We further demonstrated that PKN2, one of the PKC subtypes, was highly expressed in TNBC cell lines, and knocking down PKN2 in TNBC cells inhibited colony formation and xenograft growth. This indicates that PKN2 is required for the survival of TNBC cells, and could be the target mediates the selective activity of chelerythrine. Finally, combination of chelerythrine and chemotherapy reagent taxol showed synergistic/additive effect on TNBC cell lines. Our results suggest chelerythrine or other PKC inhibitors may be promising regimens for TNBC tumors.
Development of a Whole Organism Platform for Phenotype-Based Analysis of IGF1R-PI3K-Akt-Tor Action
May 18, 2017   Scientific Reports
Liu C, Dai W, Bai Y, Chi C, Xin Y, He G, Mai K, Duan C
Development of a Whole Organism Platform for Phenotype-Based Analysis of IGF1R-PI3K-Akt-Tor Action
May 18, 2017
Scientific Reports
Aberrant regulation of the insulin-like growth factor (IGF)/insulin (IIS)-PI3K-AKT-TOR signaling pathway is linked to major human diseases, and key components of this pathway are targets for therapeutic intervention. Current assays are molecular target- or cell culture-based platforms. Due to the great in vivo complexities inherited in this pathway, there is an unmet need for whole organism based assays. Here we report the development of a zebrafish transgenic line, Tg(igfbp5a:GFP), which faithfully reports the mitotic action of IGF1R-PI3K-Akt-Tor signaling in epithelial cells in real-time. This platform is well suited for high-throughput assays and real-time cell cycle analysis. Using this platform, the dynamics of epithelial cell proliferation in response to low [Ca2+] stress and the distinct roles of Torc1 and Torc2 were elucidated. The availability of Tg(igfbp5a:GFP) line provides a whole organism platform for phenotype-based discovery of novel players and inhibitors in the IIS-PI3K-Akt-Tor signaling pathway.
BNIP3L promotes cardiac fibrosis in cardiac fibroblasts through [Ca2+]i-TGF-β-Smad2/3 pathway
May 16, 2017   Scientific Reports
Liu W, Wang X, Mei Z, Gong J, Huang L, Gao X, Zhao Y, Ma J, Qian L
BNIP3L promotes cardiac fibrosis in cardiac fibroblasts through [Ca2+]i-TGF-β-Smad2/3 pathway
May 16, 2017
Scientific Reports
Fibrosis is an important, structurally damaging event that occurs in pathological cardiac remodeling, leading to cardiac dysfunction. BNIP3L is up-regulated in pressure overload-induced heart failure and has been reported to play an important role in cardiomyocyte apoptosis; however, its involvement in cardiac fibroblasts (CFs) remains unknown. We prove for the first time that the expression of BNIP3L is significantly increased in the CFs of rats undergoing pressure overload-induced heart failure. Furthermore, this increased BNIP3L expression was confirmed in cultured neonatal rat CFs undergoing proliferation and extracellular matrix (ECM) protein over-expression that was induced by norepinephrine (NE). The overexpression or suppression of BNIP3L promoted or inhibited NE-induced proliferation and ECM expression in CFs, respectively. In addition, [Ca2+]i, transforming growth factor beta (TGF-β) and the nuclear accumulation of Smad2/3 were successively increased when BNIP3L was overexpressed and reduced when BNIP3L was inhibited. Furthermore, the down-regulation of TGF-β by TGF-β-siRNA attenuated the increase of BNIP3L-induced fibronectin expression. We also demonstrated that the increase of BNIP3L in CFs was regulated by NE-AR-PKC pathway in vitro and in vivo. These results reveal that BNIP3L is a novel mediator of pressure overload-induced cardiac fibrosis through the [Ca2+]i-TGF-β-Smad2/3 pathway in CFs.
Flatbed epi relief-contrast cellular monitoring system for stable cell culture
May 16, 2017   Scientific Reports
Osaki T, Kageyama T, Shimazu Y, Mysnikova D, Takahashi S, Takimoto S, Fukuda J
Flatbed epi relief-contrast cellular monitoring system for stable cell culture
May 16, 2017
Scientific Reports
Consistent cell preparation is a fundamental preliminary step for understanding complex cellular mechanisms in various cell-based research fields, including basic cell biology, cancer research, and tissue engineering. However, certain elusive factors, such as cellular de-differentiation and contamination with mycoplasma or other types of cells, have compromised the reproducibility and reliability of cell-based approaches. Here, we propose an epi relief-contrast cellular monitoring system (eRC-CMS) that allows images of cells in a typical culture plate to be acquired, stored, and analysed for daily cell quality control. Due to its full flatbed nature and automated system, cells placed at any location on the stage can be analysed without special attention. Using this system, changes in the size, circularity, and proliferation of endothelial cells in subculture were recorded. Analyses of images of ~9,930,000 individual cells revealed that the growth activity and cell circularity in subcultures were closely correlated with their angiogenic activity in a subsequent hydrogel assay, demonstrating that eRC-CMS is useful for assessing cell quality in advance. We further demonstrated that eRC-CMS was feasible for the imaging of neurite elongation and spheroid formation. This system may provide a robust and versatile approach for daily cell preparation to facilitate reliable and reproducible cell-based studies.
Induction of senescence in primary glioblastoma cells by serum and TGFβ
May 20, 2017   Scientific Reports
Kumar R, Gont A, Perkins TJ, Hanson JEL, Lorimer IAJ
Induction of senescence in primary glioblastoma cells by serum and TGFβ
May 20, 2017
Scientific Reports
Glioblastoma is the most common type of adult brain tumour and has a median survival after diagnosis of a little more than a year. Glioblastomas have a high frequency of mutations in the TERT promoter and CDKN2A locus that are expected to render them resistant to both replicative and oncogene-induced senescence. However, exposure of PriGO8A primary glioblastoma cells to media with 10% serum induced a senescence-like phenotype characterized by increased senescence-associated β galactosidase activity, PML bodies and p21 and morphological changes typical of senescence. Microarray expression analysis showed that 24 h serum exposure increased the expression of genes associated with the TGFβ pathway. Treatment of PriGO8A cells with TGFβ was sufficient to induce senescence in these cells. The response of PriGO8A cells to serum was dependent on basal expression of the TGFβ activator protein thrombospondin. Primary glioblastoma cells from three additional patients showed a variable ability to undergo senescence in response to serum. However all were able to undergo senescence in response to TGFβ, although for cells from one patient this required concomitant inhibition of Ras pathway signalling. Primary glioblastoma cells therefore retain a functional senescence program that is inducible by acute activation of the TGFβ signalling pathway.

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