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Ye H.,Beijing Jiaotong University | Ye H.,Beijing Institute of Biotechnology | Ye H.,Shanghai University
Oncogene | Year: 2014

Although the activation of Ras pathway is frequently observed in human hepatocellular carcinoma (HCC), the in vivo role of Ras activation in HCC initiation and progression is underdetermined. To test the consequence of Kras activation in hepatocyte, we generated a hepatocyte-specific Kras(G12D) transgenic mouse strain and observed spontaneous development of HCC in these mice. Remarkably, HBV X protein (HBx) expression significantly promotes the formation and malignant progression of Kras(G12D)-driven HCC as shown with the accelerated tumor onset, the increased tumor burden and the more poorly differentiated lesions. At the cellular level, concomitant expression of Kras(G12D) and HBx results in a robust increase in hepatocellular proliferation. We reveal that the Akt, MAPK, p53 and TGF-β pathways are deregulated in the Kras(G12D)-driven HCCs. Also, the dysregulation is more pronounced in the HCCs developed in Kras(G12D) and HBx double transgenic mice. In addition, the altered expressions of β-catenin, CD44 and E-cadherin are only observed in the Kras(G12D) and HBx double transgenic mice. These results demonstrate a crucial role of Ras activation in hepatocellular carcinogenesis and the functional synergy between Kras(G12D) and HBx in HCC initiation and progression. The novel genetic mouse models that closely recapitulate the histopathologic progression and molecular alterations of human HCC may potentially facilitate the future therapeutic studies.


Wang J.,Beijing Institute of Biotechnology | Yang X.,Beijing Institute of Biotechnology | Yang X.,Shanghai JiaoTong University
Cellular and Molecular Life Sciences | Year: 2012

Cardiac hypertrophy is an adaptive enlargement of the myocardium in response to altered stress or injury. The cellular responses of cardiomyocytes and noncardiomyocytes to various signaling pathways should be tightly and delicately regulated to maintain cardiac homeostasis and prevent pathological cardiac hypertrophy. MicroRNAs (miRNAs) are endogenous, single-stranded, short non-coding RNAs that act as regulators of gene expression by promoting the degradation or inhibiting the translation of target mRNAs. Recent studies have revealed expression signatures of miRNAs associated with pathological cardiac hypertrophy and heart failure in humans and mouse models of heart diseases. Increasing evidence indicates that dysregulation of specific miRNAs could alter the cellular responses of cardiomyocytes and non-cardiomyocytes to specific signaling upon the pathological hemodynamic overload, leading to cardiac hypertrophy and heart failure. This review summarizes the cell-autonomous functions of cardiomyocyte miRNAs regulated by different pathways and the roles of non-cardiomyocyte miRNAs in cardiac hypertrophy. The therapeutic effects of a number of miRNAs in heart diseases are also discussed. © 2012 The Author(s).


An experimental Ebola vaccine was highly protective against the deadly virus in a major trial in Guinea, according to results published today in The Lancet. The vaccine is the first to prevent infection from one of the most lethal known pathogens, and the findings add weight to early trial results published last year. [1] The vaccine, called rVSV-ZEBOV [2], was studied in a trial involving 11,841 people in Guinea during 2015. Among the 5,837 people who received the vaccine, no Ebola cases were recorded 10 days or more after vaccination [3]. In comparison, there were 23 cases 10 days or more after vaccination among those who did not receive the vaccine. The trial was led by the World Health Organization, together with Guinea's Ministry of Health and other international partners. "While these compelling results come too late for those who lost their lives during West Africa's Ebola epidemic, they show that when the next Ebola outbreak hits, we will not be defenceless," said Dr Marie-Paule Kieny, WHO's Assistant Director-General for Health Systems and Innovation, and the study's lead author [4]. The vaccine's manufacturer, Merck, Sharpe & Dohme, this year received Breakthrough Therapy Designation from the United States Food and Drug Administration and PRIME status from the European Medicines Agency, enabling faster regulatory review of the vaccine once it is submitted. Since Ebola virus was first identified in 1976, sporadic outbreaks have been reported in Africa. But the 2013-2016 West African Ebola outbreak, which resulted in more than 11,300 deaths, highlighted the need for a vaccine. The trial took place in the coastal region of Basse-Guinée, the area of Guinea still experiencing new Ebola cases when the trial started in 2015. The trial used an innovative design, a so-called "ring vaccination" approach - the same method used to eradicate small pox. When a new Ebola case was diagnosed, the research team traced all people who may have been in contact with that case within the previous 3 weeks, such as people who lived in the same household, were visited by the patient, or were in close contact with the patient, their clothes or linen, as well as certain "contacts of contacts". A total of 117 clusters (or "rings") were identified, each made up of an average of 80 people. Initially, rings were randomised to receive the vaccine either immediately or after a 3-week delay, and only adults over 18 years were offered the vaccine. After interim results were published showing the vaccine's efficacy, all rings were offered the vaccine immediately and the trial was also opened to children older than 6 years. In addition to showing high efficacy among those vaccinated, the trial also shows that unvaccinated people in the rings were indirectly protected from Ebola virus through the ring vaccination approach (so-called "herd immunity"). However, the authors note that the trial was not designed to measure this effect, so more research will be needed. "Ebola left a devastating legacy in our country. We are proud that we have been able to contribute to developing a vaccine that will prevent other nations from enduring what we endured" said Dr KeÏta Sakoba, Coordinator of the Ebola Response and Director of the National Agency for Health Security in Guinea [4]. To assess safety, people who received the vaccine were observed for 30 minutes after vaccination, and at repeated home visits up to 12 weeks later. Approximately half reported mild symptoms soon after vaccination, including headache, fatigue and muscle pain but recovered within days without long-term effects. Two serious adverse events were judged to be related to vaccination (a febrile reaction and one anaphylaxis) and one was judged to be possibly related (influenza-like illness). All three recovered without any long term effects. It was not possible to collect biological samples from people who received the vaccine in order to analyse their immune response. Other studies are looking at the immune response to the vaccine including one conducted in parallel to the ring trial among frontline Ebola workers in Guinea. "This both historical and innovative trial was made possible thanks to exemplary international collaboration and coordination, the contribution of many experts worldwide, and strong local involvement," said Dr John-Arne Røttingen, Specialist Director at the Norwegian Institute of Public Health, and the chairman of the study steering group [4]. In January, GAVI, the Vaccine Alliance provided US$5 million to Merck towards the future procurement of the vaccine once it is approved, prequalified and recommended by WHO. As part of this agreement, Merck committed to ensure that 300,000 doses of the vaccine are available for emergency use in the interim, and to submit the vaccine for licensure by the end of 2017. Merck has also submitted the vaccine to WHO's Emergency Use and Assessment Listing procedure, a mechanism through which experimental vaccines, medicines and diagnostics can be made available for use prior to formal licensure. Additional studies are ongoing to provide more data on the safety of the vaccine in children and other vulnerable populations such as people with HIV. In case of Ebola flare-ups prior to approval, access to the vaccine is being made available through a procedure called "compassionate use" that enables use of the vaccine after informed consent. Merck and WHO's partners are working to compile data to support license applications. The rapid development of rVSV-EBOV contributed to the development of WHO's R&D Blueprint, a global strategy to fast-track the development of effective tests, vaccines and medicines during epidemics. Also published in The Lancet (embargo as above), is a phase 2 trial of a different Ebola vaccine candidate, the recombinant adenovirus type-5 Ebola vaccine. The trial was led by the Beijing Institute of Biotechnology and was conducted in Sierra Leone in 2015. It involved 500 healthy participants, followed for 6 months - 250 were given a high dose vaccine, 125 a low-dose and 125 a placebo. The study found that the vaccine was safe and induced an immune response that peaked at 28 days, but decreased during the six months post injection. One serious adverse event was reported, in an individual with a history of asthma. Further research on this vaccine is needed in order to assess its efficacy. The rVSV-ZEBOV trial is funded by WHO, with support from the Wellcome Trust, the United Kingdom Department for International Development, the Norwegian Ministry of Foreign Affairs to the Norwegian Institute of Public Health through the Research Council of Norway, the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development and Médecins Sans Frontières. The trial team includes experts from The University of Bern, the University of Florida, the London School of Hygiene and Tropical Medicine, Public Health England, the European Mobile Laboratories among others. The trial was designed by a group of experts including the late Professor Donald A. Henderson of John Hopkins University, who led the WHO smallpox eradication effort by using the ring vaccination strategy. [1] http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)61117-5/abstract [2] VSV-EBOV was developed by the Public Health Agency of Canada. The vaccine was licensed to NewLink Genetics, who in turn licensed it to Merck & Co. The vaccine works by replacing a gene from a harmless virus known as vesicular stomatitis virus (VSV) with a gene encoding an Ebola virus surface protein. The vaccine does not contain any live Ebola virus. Earlier trials have shown the vaccine to be protective in animals, and be safe and produce an immune response in humans. [3] Analysis only included cases occurring 10 days after receiving the vaccine to account for the incubation period of the Ebola virus. [4] Quotes direct from authors and cannot be found in the text of the Article.


Wang Z.,Beijing Institute of Biotechnology | Sun Y.,University of Michigan
Translational Oncology | Year: 2010

Carcinogenesis is a multistage process, involving oncogene activation and tumor suppressor gene inactivation as well as complex interactions between tumor and host tissues, leading ultimately to an aggressive metastatic phenotype. Among many genetic lesions, mutational inactivation of p53 tumor suppressor, the "guardian of the genome," is the most frequent event found in 50%of human cancers. p53 plays a critical role in tumor suppression mainly by inducing growth arrest, apoptosis, and senescence, as well as by blocking angiogenesis. In addition, p53 generally confers the cancer cell sensitivity to chemoradiation. Thus, p53 becomes the most appealing target for mechanism-driven anticancer drug discovery. This review will focus on the approaches currently undertaken to target p53 and its regulators with an overall goal either to activate p53 in cancer cells for killing or to inactivate p53 temporarily in normal cells for chemoradiation protection. The compounds that activate wild type (wt) p53 would have an application for the treatment of wt p53-containing human cancer. Likewise, the compounds that change p53 conformation from mutant to wt p53 (p53 reactivation) or that kill the cancer cells with mutant p53 using a synthetic lethal mechanism can be used to selectively treat human cancer harboring a mutant p53. The inhibitors of wt p53 can be used on a temporary basis to reduce the normal cell toxicity derived from p53 activation. Thus, successful development of these three classes of p53 modulators, to be used alone or in combination with chemoradiation, will revolutionize current anticancer therapies and benefit cancer patients. Copyright © 2010 Neoplasia Press, Inc. All rights reserved.


Li Z.,Beijing Institute of Biotechnology
Cell Death and Differentiation | Year: 2015

Basal autophagy is tightly regulated by transcriptional and epigenetic factors to maintain cellular homeostasis. Dysregulation of cardiac autophagy is associated with heart diseases, including cardiac hypertrophy, but the mechanism governing cardiac autophagy is rarely identified. To analyze the in vivo function of miR-199a in cardiac autophagy and cardiac hypertrophy, we generated cardiac-specific miR-199a transgenic mice and showed that overexpression of miR-199a was sufficient to inhibit cardiomyocyte autophagy and induce cardiac hypertrophy in vivo. miR-199a impaired cardiomyocyte autophagy in a cell-autonomous manner by targeting glycogen synthase kinase 3β (GSK3β)/mammalian target of rapamycin (mTOR) complex signaling. Overexpression of autophagy related gene 5 (Atg5) attenuated the hypertrophic effects of miR-199a overexpression on cardiomyocytes, and activation of autophagy using rapamycin was sufficient to restore cardiac autophagy and decrease cardiac hypertrophy in miR-199a transgenic mice. These results reveal a novel role of miR-199a as a key regulator of cardiac autophagy, suggesting that targeting miRNAs controlling autophagy as a potential therapeutic strategy for cardiac disease.Cell Death and Differentiation advance online publication, 10 July 2015; doi:10.1038/cdd.2015.95. © 2015 Macmillan Publishers Limited


Li X.-B.,Beijing Institute of Biotechnology
Cell Research | Year: 2016

The cellular origin of gastric cancer remains elusive. Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is the first identified marker of gastric stem cells. However, the role of Lgr5+ stem cells in driving malignant gastric cancer is not fully validated. Here, we deleted Smad4 and PTEN in murine gastric Lgr5+ stem cells by the inducible Cre-LoxP system and marked mutant Lgr5+ stem cells and their progeny with Cre-reporter Rosa26tdTomato. Rapid onset and progression from microadenoma and macroscopic adenoma to invasive intestinal-type gastric cancer (IGC) were found in the gastric antrum with the loss of Smad4 and PTEN. In addition, invasive IGC developed at the murine gastro-forestomach junction, where a few Lgr5+ stem cells reside. In contrast, Smad4 and PTEN deletions in differentiated cells, including antral parietal cells, pit cells and corpus Lgr5+ chief cells, failed to initiate tumor growth. Furthermore, mutant Lgr5+ cells were involved in IGC growth and progression. In the TCGA (The Cancer Genome Atlas) database, an increase in LGR5 expression was manifested in the human IGC that occurred at the gastric antrum and gastro-esophageal junction. In addition, the concurrent deletion of SMAD4 and PTEN, as well as their reduced expression and deregulated downstream pathways, were associated with human IGC. Thus, we demonstrated that gastric Lgr5+ stem cells were cancer-initiating cells and might act as cancer-propagating cells to contribute to malignant progression.Cell Research advance online publication 19 April 2016; doi:10.1038/cr.2016.47. © 2016 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences


Yang G.,Beijing Institute of Biotechnology | Yang X.,Beijing Institute of Biotechnology
International Journal of Biological Sciences | Year: 2010

Transforming growth factor-β (TGF-β) family members exert their function via specific type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors, including the common mediator Smad4. The dual effects of TGF-β signaling on tumor initiation and progression are cell-specific and yet to be determined under distinct contexts. A number of genetically manipulated mouse models with alterations in the TGF-β pathway genes, particularly the pivotal Smad4, revealed that these genes play crucial functions in maintaining tissue homeostasis and suppressing tumorigenesis. Loss of Smad4 plays a causal role in initiating squamous cell carcinomas of skin and upper digestive tract as well as ade-nocarcinomas of gastrointestinal tract. However, for some cancers like pancreatic and cholangiocellular carcinomas, Smad4 deficiency does not initiate the tumorigenesis but acts as a promoter to accelerate or synergize the development and progression of cancers that are started by other oncogenic pathways. Intriguingly, emerging evidences from mouse models have highlighted the important roles of non-cell autonomous effects of Smad4-mediated TGF-β signaling in the inhibition of oncogenesis. All these data have greatly deepened our understanding of molecular mechanisms of cell-autonomous and non-cell autonomous effect of Smad4-mediated TGF-β signaling in suppressing carcinogenesis, which may facilitate the development of successful therapies targeting TGF-β signaling for the treatment of human cancers. © Ivyspring International Publisher.


Huang H.,Capital Medical University | Chen Z.,Beijing Institute of Biotechnology | Sun Q.,Beijing Institute of Biotechnology
Current Molecular Medicine | Year: 2015

Cell competition was first identified four decades ago as a mechanism to eliminate less fit cells during development in Drosophila melanogaster, and later postulated to be involved in tumorigenesis of human beings. However, evidence for a similar mechanism functional in mammals and tumors was missed until recent years. Like cell competition in fly, multiple forms of competition mechanisms were reported in mammalian system, and some of them were found participating in tumor initiation. Lately, entosis, a mechanism of cell cannibalisms responsible for the formation of cell-in-cell structures in human tumors, was identified as a novel member of ever-expanding family of mammalian cell competitions (MaCCs), and proposed to be able to promote clonal selection and tumor evolution. Thus, engulfment by neighboring cells other than the professional phagocytes, an issue still in debate in fly, was clearly demonstrated in mammals to be responsible for loser elimination. Competition mediated by cell-in-cell structures, formed by multiple cannibal mechanisms, constitutes a novel class of MaCCs. This review will summarize current research on mammalian cell competitions, followed by feature and mechanism analysis and their potential implications in the pathology and treatment of human tumors. © 2015 Bentham Science Publishers.


Qian X.,Beijing Institute of Biotechnology
PloS one | Year: 2012

Prostate-specific antigen (PSA) screening, although common, has recently been called into question. To find prostate cancer (PCa) diagnostic biomarkers that can make up for the defects of PSA, we compared the secretomes of several benign and PCa cell lines, selected candidate molecules, and then confirmed their clinical value. We first identified extracellular proteins by two-dimensional gel electrophoresis (2-DE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification. We then validated the secreted proteins on a cellular level, and finally determined whether they could be used as PCa diagnostic biomarkers using prostate tissue and serum specimens of Chinese volunteers by immunohistostaining and sandwich ELISA. We obtained credible extracellular protein 2-DE graphs of prostate cell lines. The 5 spots that showed superior repeatability were selected for LC-MS/MS analysis, which identified seven candidate molecules. One of the candidate molecules, spondin-2 (SPON2), was only expressed in the conditioned media (CM) of androgen receptor (AR) positive PCa cell lines. Using tissue microarray by immunohistostaining, we found SPON2 to be over-expressed in PCa. SPON2 staining was more intense in Gleason score sum 7-8 and in PCa patients with metastasis. By receiver operator characteristic (ROC) curve analysis, we found that the serum SPON2 level was elevated in PCa patients, showing sensitivity and specificity suitable for diagnostic use. We also found that SPON2 could be used to identify PCa patients with serum PSA levels no higher than 10 ng/ml from healthy elderly men. SPON2 is a new serum and histological diagnostic biomarker for PCa. It can avoid some of the problems of PSA testing and was here found to offer relatively high sensitivity and specificity relative to PSA.


Hou N.,Beijing Institute of Biotechnology
Yi chuan = Hereditas / Zhongguo yi chuan xue hui bian ji | Year: 2012

Previous microRNA (miRNA) array results have shown that the expression of miR-27b is upregulated in heart tissues from human cardiomyopathy and pressure-overloaded hypertrophic mouse model, implying that miR-27b might play an important role in heart diseases. To study the in vivo function of miR-27b, we generated a transgenic mouse line overexpressing miR-27b under the control of the 5.5 kb promoter of a-myosin heavy chain (a-MHC). Real-time PCR results demonstrated that miR-27b precursor and mature miR-27b were significantly increased in the heart tissues of miR-27b transgenic mice. miR-27b transgenic mice not only displayed cardiac hypertrophy, but also exhibited significant cardiac fibrosis. Further study showed that matrix metalloproteinase 13 (MMP13), a key regulator involved in cardiac fibrosis, was the target of miR-27b. The expression of MMP13 was decreased and the expression of Col I and III was increased in miR-27b transgenic mice.. In addition, defects in ultrastructral architecture were also found in miR-27b trans-genic mice. The above results demonstrated that miR-27b might promote cardiac fibrosis through inhibiting MMP13.

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