مجال
التميز
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تميز دراسي وبحثي وإبداع علمي
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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Tumor hypoxia induces nuclear paraspeckle
formation through HIF-2α dependent transcriptional activation of NEAT1
leading to cancer cell survival
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رابط إلى البحث:
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Click
here
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تاريخ النشر:
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10/10/2014
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موجز عن البحث:
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Activation of cellular transcriptional
responses, mediated by hypoxia-inducible factor (HIF), is common in many
types of cancer, and generally confers a poor prognosis. Known to induce many
hundreds of protein-coding genes, HIF has also recently been shown to be a
key regulator of the non-coding transcriptional response. Here, we show that
NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF
in many breast cancer cell lines and in solid tumors. Unlike previously
described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by
HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of
paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation
in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are
multifunction nuclear structures that sequester transcriptionally active
proteins as well as RNA transcripts that have been subjected to
adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of
one such transcript, F11R (also known as junctional adhesion molecule 1,
JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby
conferring a novel mechanism of HIF-dependent gene regulation. Induction of
NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved
clonogenic survival and reduced apoptosis, all of which are hallmarks of
increased tumorigenesis. Furthermore, in patients with breast cancer, high
tumor NEAT1 expression correlates with poor survival. Taken together, these
results indicate a new role for HIF transcriptional pathways in the
regulation of nuclear structure and that this contributes to the pro-tumorigenic
hypoxia-phenotype in breast cancer.
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المؤتمرات العلمية:
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المؤتمر (1):
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عنوان المؤتمر:
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NCRI 2014
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تاريخ الإنعقاد:
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02/11/2014
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مكان
الإنعقاد:
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Liverpool, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Targeting EGFR in triple negative breast
cancer: understanding both acute and chronic responses
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ملخص المشاركة:
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Background:
Epidermal
growth factor receptor (EGFR) is frequently overexpressed in the majority of
triple negative breast cancer patients (TNBC). However, the molecular
determinants behind their limited response to EGFR-targeted therapies are
poorly understood. Here, both the acute and chronic responses of TNBC to
EGFR-targeted therapy, cetuximab, have been investigated.
Method:
The
expression of EGFR has been analysed in a cohort of 2000 breast cancer
patients as well as in breast cancer cell lines. Furthermore, response of
TNBC cell lines to cetuximab has been investigated using conventional
biochemical methods. Moreover, a comprehensive transcriptomic profiling of
acquired cetuximab-resistant TNBC model has been used to understand the
molecular determinants of acquired-cetuximab resistance.
Results:
Here,
we confirmed that EGFR is highly expressed in TNBC in comparison to non-TNBC
breast cancer patients and cell lines, which was associated with adverse
clinical outcomes. Targeting EGFR in TNBC cell lines using cetuximab failed
to completely inhibit EGFR signalling pathway and was associated with an
increase in ADAMs-mediated endogenous ligand release. Inhibition of ADAMs
significantly enhanced the antitumor efficacy of cetuximab both in vitro and
in vivo. Furthermore, transcriptomic profiling of our acquired-cetuximab
resistant TNBC cell line (MDA-MB-468CR) using RNA-seq revealed an activation
of several key oncogenic pathways and genes including the TGF-beta/BMP
pathway, which has been correlated with the public available dataset of
cetuximab-treated TNBC patients. Blocking BMP receptors (BMPRs) restored the
sensitivity of resistant cells to cetuximab treatment.
Conclusion:
Collectively, although clinical trials
testing cetuximab reported lack of benefit in TNBC, our findings offer
alternative strategies that could enhance the initial response to cetuximab
in TNBC. Also, our finding highlighted the key changes in the acquired-cetuximab
resistant TNBC transcriptome that might be involved in the resistance
mechanisms. We further reported that
simultaneous targeting of both EGFR and BMPR pathways could overcome
cetuximab-resistance with important implications for the treatment of TNBC.
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المؤتمر (2):
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عنوان المؤتمر:
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Breakthrough Breast Cancer TNBC Cancer
Conference 2013
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تاريخ الإنعقاد:
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26/06/2013
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مكان
الإنعقاد:
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London, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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High throughput RNA sequencing of Cetuximab
Resistance Triple Negative Breast Cancer
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ملخص المشاركة:
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Triple negative breast cancer (TNBC) is a
sub-molecular type of breast cancer that is defined by the absence of
oestrogen receptor (ER), progesterone receptor (PR) and HER2
amplification. The high expression of
epidermal growth factor receptor (EGFR) in TNBC patients (60–70%) makes it a
good candidate for targeted therapy. However, clinical trials have shown a
poor response rate of cetuximab, an anti-EGFR antibody, as a single agent or
in combination with chemotherapy in these patients. In this study, we
compared the EGFR expression and cetuximab sensitivity in a panel of TNBC
cell lines. Among the investigated cell lines, we found MDA-MB-468 was highly
sensitive to cetuximab compare to other TNBC cell lines. Additionally, we have developed a model of
cetuximab-acquired resistant TNBC, named MDA-MB-468CR, which was resistant to
cetuximab in comparison to the parental MDA-MB-468 cell line. Resistant cells
were morphologically similar to parental MDA-MB-468 cells with a slight
increase in their growth rate. Using a next generation RNA sequencing
approach, we compared the transcriptome of MDA-MB-468CR and MDA-MB-468 TNBC
cells to identify the deregulated genes and pathways that might be involved
in the development of cetuximab resistance. We identified 1476 genes (71.47%
up-regulated and 28.52% down-regulated, FDR<0.05) that were significantly
differentially-expressed between the parental and resistant cell lines.
Up-regulated genes were clustered into several pathways including; p53
signaling pathway, ErbB signaling pathway, Cell cycle, TGF-beta signaling
pathway and apoptosis. Moreover, we found a down-regulation in EGR1 gene,
which is suggested as a cancer suppressor gene. We then correlated our findings
with the public dataset from TNBC patient that have been treated with
cetuximab. In conclusion, our preliminary data indicated an up-regulation of
several pathways in cetuximab-acquired resistant cells that might be
responsible for the development of this resistance and suggested further
studies of these activated pathways in order to find different drug
combinations to overcome the resistant mechanisms.
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جوائز التكريم:
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الجائزة (1):
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مسمى الجائزة:
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Selection for poster walk
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الجهة المانحة:
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Breakthrough Breast Cancer TNBC Cancer
Conference 2013
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تاريخ الجائزة:
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26/06/2013
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مجال التكريم:
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High throughput RNA sequencing of cetuximab
resistant triple negative breast cancer
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الجائزة (2):
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مسمى الجائزة:
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Second best poster – Medical Science
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الجهة المانحة:
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The 7th Saudi Student Conference
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تاريخ الجائزة:
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01/02/2014
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مجال التكريم:
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Transcriptome landscape of
cetuximab-resistant triple negative breast cancer cells revealed deregulation
of TGF-beta pathway
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