Tumor suppressor functions of BNip3 in hepatocellular carcinoma /
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Author / Creator: | Drake, Lauren Elizabeth, author. |
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Imprint: | 2015. Ann Arbor : ProQuest Dissertations & Theses, 2015 |
Description: | 1 electronic resource (146 pages) |
Language: | English |
Format: | E-Resource Dissertations |
Local Note: | School code: 0330 |
URL for this record: | http://pi.lib.uchicago.edu/1001/cat/bib/10862858 |
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100 | 1 | |a Drake, Lauren Elizabeth, |e author. | |
245 | 1 | 0 | |a Tumor suppressor functions of BNip3 in hepatocellular carcinoma / |c Drake, Lauren Elizabeth. |
260 | |c 2015. | ||
264 | 1 | |a Ann Arbor : |b ProQuest Dissertations & Theses, |c 2015 | |
300 | |a 1 electronic resource (146 pages) | ||
336 | |a text |b txt |2 rdacontent | ||
337 | |a computer |b c |2 rdamedia | ||
338 | |a online resource |b cr |2 rdacarrier | ||
500 | |a Advisors: Kay F. Macleod Committee members: Matthew Brady; Mark Lingen; Catherine Reardon. | ||
502 | |b Ph.D. |c University of Chicago, Division of the Biological Sciences, Department of Pathology |d 2015. | ||
506 | |a This item is not available from ProQuest Dissertations & Theses. | ||
510 | 4 | |a Dissertation Abstracts International, |c Volume: 77-10(E), Section: B. | |
520 | |a BNip3 is a mitochondrial protein that promotes the turnover of mitochondria at the autophagolysosome through an interaction with the core autophagy protein LC3. BNip3 is expressed under normal conditions in the liver and is increased and stabilized downstream of fasting signals to reduce mitochondrial content when nutrient supplies are low. Deletion of BNip3 leads to accumulation of dysfunctional mitochondria and increased lipid droplets in the liver that closely mimics human non-alcoholic steatohepatitis, a precursor disease for development of hepatocellular carcinoma (HCC). | ||
520 | |a HCC is the fifth most common cause of cancer and the third leading cause of cancer-associated death, worldwide. Understanding the molecular mechanisms leading to HCC initiation and progression is greatly needed in order to improve therapeutic strategies and increase overall survival in patients with HCC. This can be achieved by better stratification of patients into groups most likely to benefit from certain therapies, and also by identification of novel therapeutic targets essential to the growth of HCC tumors. | ||
520 | |a BNIP3 silencing has been observed in HCC and several other malignancies and often correlates with more aggressive tumors and worse outcomes. However, the functional significance of BNIP3 loss on tumor growth and progression has not been studied in HCC. The work presented in this thesis provides evidence that BNip3 is a tumor suppressor in HCC through two independent mechanisms. First, we show that BNip3 suppresses tumor initiation by limiting DNA damage and cell death in response to the liver carcinogen diethylnitrosamine (DEN). Developing BNip3 null livers were found to have increased levels of proliferation thus leading to genomic instability and increased susceptibility to DNA damage following treatment with DEN. This increased DNA damage leads to increased cell death, which in turn promotes compensatory proliferation and HCC tumor initiation, resulting in increased tumor burden in the BNip3 null mice at 6 months of age. Secondly, we identify a role for BNip3 in suppressing lipid synthesis leading to reduced proliferation and development of smaller tumors. Restoration of BNip3 expression in a primary HCC cell line reduced lipogenesis and increased oxygen consumption and additionally reduced the rate of cell growth, suggesting that loss of BNip3 promotes the Warburg effect to support increased lipid synthesis required for proliferation. Furthermore, the increased lipogenesis observed in the BNip3 null tumors suggests that BNIP3-silenced tumors in human HCC may be excellent candidates for treatment with fatty acid synthase inhibitors. | ||
546 | |a English | ||
590 | |a School code: 0330 | ||
690 | |a Pathology. | ||
690 | |a Oncology. | ||
690 | |a Physiology. | ||
690 | |a Molecular biology. | ||
690 | |a Cellular biology. | ||
710 | 2 | |a University of Chicago. |e degree granting institution. | |
720 | 1 | |a Kay F. Macleod |e degree supervisor. | |
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