Document Details
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Document Type |
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Thesis |
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Document Title |
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ELUCIDATING THE ROLE OF SIGNAL TRANSDUCTION PATHWAYS OF CANCER STEM CELLS DURING METASTASIS IN BREAST CANCER توضيح دور مسارات نقل الاشارة من الخلايا الجذعية السرطانية خلال انتشار سرطان الثدي |
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Subject |
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Faculty of Sciences |
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Document Language |
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Arabic |
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Abstract |
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How disseminated cancer stem cells (CSCs) in circulation initiate breast cancer metastasis, still remains an enigma. Therefore, current new drug discovery efforts are directed towards targeting specific gene(s) in the signaling pathways involved in survival, invasion, self-renewal, and metastatic processes. First of all, we carried out a pilot Bioinformatics study to evaluate the differential gene expression patterns found between a normal epithelial cell line-MCF10 A and a breast cancer cell line-MCF7. We mainly focused on CEACAM6 (Carcinoembryonic antigen related cell adhesion molecule 6) and CEACAM5 (Carcinoembryonic antigen related cell adhesion molecule 5) both of which are presumably pre-requisites for invasive and metastatic behavior of breast cancer. A 4.5-fold up-regulation in CEACAM5 expression while 7-fold increase was recorded for CEACAM6 expression. We propose that the up-regulation of both these proteins in MCF7 cell line compared to MCF10A implicates their inconspicuous role in tumorigenesis, enhanced invasiveness and thus, leading to increased propensity towards breast cancer metastasis. This gave us clues to examine the anti-metastatic potential of individual small molecule compound, extracted from Rhazya stricta, a traditional medicinal plant. Spectroscopic study, including NMR (Nuclear magnetic resonance) and ATR-FTIR (Attenuated total reflectance Fourier transform infrared spectroscopy) was performed to elucidate the structure of newly isolated small molecule compound (Rhazyaminine). Total alkaloid extract (TERS) and Rhazyaminine (R.A) treatments were used for growth kinetic studies of MCF7 cell line in a dose dependent manner, followed by scratch assays for cell migration analyses. In addition, RNA-Seq analysis of MCF7 cell line treated with R.A validated the its anti-metastatic potential as a number of genes involved in the signal transduction cascade of metastasis were prime targets. Down-regulation of Bcl-2, an anti-apoptotic gene, also involved in metastasis, was validated using qPCR. To our knowledge, this is the first study, which pinpoints the role of R.A in down-regulating key genes involved in apoptosis, cell survival, EMT (epithelial-to-mesenchymal transition), CSCs (Cancer stem cells) proliferation and Wnt signal transduction pathway. Further studies using in vitro and in vivo models of breast cancer metastasis will bring us a step closer to developing new drugs targeting CSCs related genes. |
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Supervisor |
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Prof. Kulvinder Singh Saini |
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Thesis Type |
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Doctorate Thesis |
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Publishing Year |
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1439 AH
2018 AD |
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Co-Supervisor |
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Prof. Saleh Al-karim |
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Added Date |
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Wednesday, January 10, 2018 |
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Researchers
| وقاص اقبال | Iqbal, Waqas | Researcher | Doctorate | |
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