SAN DIEGO, CA, United States
SAN DIEGO, CA, United States

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Lo J.-F.,National Yang Ming University | Lo J.-F.,Taipei Veterans General Hospital | Yu C.-C.,National Yang Ming University | Yu C.-C.,Chung Shan Medical University | And 11 more authors.
Cancer Research | Year: 2011

Cancer-initiating cells (CIC) comprise a rare subpopulation of cells in tumors that are proposed to be responsible for tumor growth. Starting from CICs identified in head and neck squamous cell carcinomas (HNSCC), termed head and neck cancer-initiating cells (HN-CIC), we determined as a candidate stemnessmaintaining molecule for HN-CICs the proinflammatory mediator S100A4, which is also known to be an inducer of epithelial-mesenchymal transition. S100A4 knockdown in HN-CICs reduced their self-renewal capability and their stemness and tumorigenic properties, both in vitro and in vivo. Conversely, S100A4 overexpression in HNSCC cells enhanced their stem cell properties. Mechanistic investigations indicated that attenuation of endogenous S100A4 levels in HNSCC cells caused downregulation of Notch2 and PI3K (phosphoinositide 3-kinase)/pAKT along with upregulation of PTEN, consistent with biological findings. Immunohistochemical analysis of HNSCC clinical specimens showed that S100A4 expression was positively correlated with clinical grading, stemness markers, and poorer patient survival. Together, our findings reveal a crucial role for S100A4 signaling pathways in maintaining the stemness properties and tumorigenicity of HN-CICs. Furthermore, our findings suggest that targeting S100A4 signaling may offer a new targeted strategy for HNSCC treatment by eliminating HN-CICs. ©2010 AACR.


Yoshizuka N.,Scripps Research Institute | Chen R.M.,Scripps Research Institute | Chen R.M.,Epitomics Inc. | Xu Z.,Scripps Research Institute | And 9 more authors.
Molecular and Cellular Biology | Year: 2012

The p38 mitogen-activated protein kinase (MAPK) pathway has been implicated in both suppression and promotion of tumorigenesis. It remains unclear how these 2 opposite functions of p38 operate in vivo to impact cancer development. We previously reported that a p38 downstream kinase, p38-regulated/activated kinase (PRAK), suppresses tumor initiation and promotion by mediating oncogene-induced senescence in a murine skin carcinogenesis model. Here, using the same model, we show that once the tumors are formed, PRAK promotes the growth and progression of skin tumors. Further studies identify PRAK as a novel host factor essential for tumor angiogenesis. In response to tumor-secreted proangiogenic factors, PRAK is activated by p38 via a vascular endothelial growth factor receptor 2 (VEGFR2)-dependent mechanism in host endothelial cells, where it mediates cell migration toward tumors and incorporation of these cells into tumor vasculature, at least partly by regulating the phosphorylation and activation of focal adhesion kinase (FAK) and cytoskeletal reorganization. These findings have uncovered a novel signaling circuit essential for endothelial cell motility and tumor angiogenesis. Moreover, we demonstrate that the tumorsuppressing and tumor-promoting functions of the p38-PRAK pathway are temporally and spatially separated during cancer development in vivo, relying on the stimulus, and the tissue type and the stage of cancer development in which it is activated. © 2012, American Society for Microbiology.


Hong L.,Xiamen University | Hong L.,Scripps Research Institute | Lai M.,Scripps Research Institute | Chen M.,Scripps Research Institute | And 8 more authors.
Cancer Research | Year: 2010

In mammalian cells, activation of oncogenes usually triggers innate tumor-suppressing defense mechanisms, including apoptosis and senescence, which are compromised by additional mutations before cancers are developed. The miR-17-92 gene cluster, a polycistron encoding six microRNAs (miRNA), is frequently overexpressed in human cancers and has been shown to promote several aspects of oncogenic transformation, including evasion of apoptosis. In the current study, we show a new role of miR-17-92 in inhibiting oncogenic ras-induced senescence. Further dissection of the miRNA components in this cluster reveals that the miR-17/20a seed family accounts for this antisenescence activity. miR-17 and miR-20a are both necessary and sufficient for conferring resistance to ras-induced senescence by directly targeting p21WAF1, a key effector of senescence. By contrast, these components are not essential for the ability of miR-17-92 to evade Myc-induced apoptosis. Moreover, disruption of senescence by miR-17-92 or its miR-17/20a components leads to enhanced oncogenic transformation by activated ras in primary human cells. Taken together with previous reports that miR-17-92 inhibits apoptosis by suppressing Pten via the miR-19 components, our results indicate that this miRNA cluster promotes tumorigenesis by antagonizing both tumor-suppressing mechanisms, apoptosis, and senescence, through the activities of different miRNA components encoded in this cluster. ©2010 AACR.


PubMed | Scripps Research Institute, Torrey Pines Institute for Molecular Studies, San Diego Biomedical Research Institute and Biosettia, Inc.
Type: | Journal: European journal of immunology | Year: 2017

Secreted microvesicles (MVs) are potent inflammatory triggers that stimulate autoreactive B and T cells, causing Type 1 Diabetes in non-obese diabetic (NOD) mice. Proteomic analysis of purified MVs released from islet cells detected the presence of endogenous retrovirus (ERV) antigens, including Env and Gag sequences similar to the well-characterized murine leukemia retroviruses. This raises the possibility that ERV antigens may be expressed in the pancreatic islets via MV secretion. Using virus-like particles produced by co-expressing ERV Env and Gag antigens, and a recombinant gp70 Env protein, we demonstrated that NOD but not diabetes-resistant mice developed anti-Env autoantibodies that increase in titer as disease progresses. A lentiviral-based RNA interference knockdown of Gag revealed that Gag contributes to the MV-induced T-cell response, whose diabetogenic function can be demonstrated via cell-transfer into immune-deficient mice. Finally, we observed that Gag and Env are expressed in NOD islet-derived primary mesenchymal stem cells (MSCs). However, MSCs derived from the islets of diabetes-resistant mice do not express the antigens. Taken together, abnormal ERV activation and secretion of MVs may induce anti-retroviral responses to trigger autoimmunity. This article is protected by copyright. All rights reserved.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 99.95K | Year: 2010

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) are naturally occurring small RNAs that regulate the expression of protein- encoding genes. They play important roles in many cellular processes, and are involved in multiple diseases such as cancer. We have developed the Biosettia Lenti-miRNA Collection, a human miRNA library that includes a nearly complete set (670 of 706) of the miRNAs known to date in a novel lentiviral expression vector. This library represents the most complete collection of miRNA among all the miRNA libraries currently available. The miRNAs in the Biosettia library are expressed from a lentiviral vector that mediates high- efficiency, stable gene transduction in both dividing and non-dividing cells. In addition, the library was generated in an individually arrayed format, which facilitates the use of the library in phenotypic screens based on negative selection, and in identification of miRNAs conferring weak phenotypes or with low penetrance. In this application, we propose to first complete the collection of miRNA in the Biosettia library, to include all the 706 currently known human miRNAs and new miRNAs discovered in the future. In addition, we will validate the application of this library in functional screens designed to identify miRNAs that inhibit the senescence- inducing activity or the pro-mitogenic activity of oncogenic ras. These screens are based on positive and negative selections of tumorigenic phenotypes, respectively. The outcomes of the proposed studies will not only validate the use of the Biosettia library as a discovery tool for miRNA functions, but also lead to identification of oncogenic and tumor-suppressing miRNAs that may serve as diagnostic markers or new therapeutic targets for cancer. PUBLIC HEALTH RELEVANCE: Studies proposed in this grant aim to complete and validate the application of a miRNA library developed at Biosettia. These studies will provide the research community with a valuable tool for analyzing the functions of miRNAs in physiological and pathological processes. The genetic screens used to validate the use of library will likely lead to identification of oncogenic and tumor-suppressing miRNAs that may serve as diagnostic markers or new therapeutic targets for cancer. '


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Online Only Sale! 20% off miRNA Control with purchase of our miRNA expression vector (use CONTROL20 at checkout) Phone: 858-345-5589 Fax: 858-345-3871 Email: info@biosettia.com


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Biosettia, Inc. | Entity website

Contact Biosettia Today Biosettia Inc. 6048 Cornerstone Court West, Suite C San Diego, CA 92121 Fax: 858-345-3871 Phone: 858-345-5589 Order: order@biosettia ...


Biosettia, Inc. | Entity website

Product Details and Specifications Product Name mir-control lentivirus (1ml) Product Catalog Number mir-LV000 Price 300.00 USD Shipping Conditions Shipped in dry ice ...


Biosettia, Inc. | Entity website

Online Only Sale! 20% off miRNA Control with purchase of our miRNA expression vector (use CONTROL20 at checkout) Phone: 858-345-5589 Fax: 858-345-3871 Email: info@biosettia.com

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