Fhit inactivation in neoplasia: <i>in vitro</i> insights into cancer initiation and progression
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The Ohio State University / OhioLINK
2016
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ndltd-OhioLink-oai-etd.ohiolink.edu-osu14673851272021-08-03T06:37:07Z Fhit inactivation in neoplasia: <i>in vitro</i> insights into cancer initiation and progression Karras, Jenna Biology The fragile <i>FHIT</i> gene, encompassing one of the most active common fragile sites, FRA3B, is frequently altered in preneoplasia and cancer, through gene rearrangements or silencing by hypermethylation of regulatory sequences. Silencing of Fhit protein expression through activation of fragile gaps and breaks in the FRA3B locus, or locus hypermethylation, causes thymidine kinase down-regulation and dNTP imbalance, resulting in spontaneous replication stress that leads to chromosomal aberrations, allele copy number variations, small insertions/deletions and single-base substitutions. Thus, Fhit, which is reduced in expression in the majority of human cancers, is a genome caretaker whose loss initiates genome instability in preneoplastic lesions creating the “soil” for cancer development. However, some scientists argue that Fhit is lost in cancers simply because of its position at a fragile locus that is very susceptible to breakage. This skepticism has hindered consideration of Fhit-associated therapeutic targets for the majority of human cancers exhibiting Fhit loss.Here we followed this process from loss of Fhit genome caretaker function, through development of genetic alterations to isolation of clones with tumorigenic potential. We established epithelial cell lines from kidney tissues of <i>Fhit<sup>-/-</sup></i> and <i>Fhit<sup>+/+</sup></i> mice early after weaning of pups, and subjected some cell lines to nutritional and carcinogen stress; the Fhit+/+ cell lines did not survive either of these additional stresses. In contrast to +/+ cells, loss of Fhit leads to alterations in apoptotic and EMT signaling pathways and oncogene activation. These alterations allow for transformation, selective clonal expansion and development of invasive properties in vitro as well as tumor formation and metastasis in vivo. Thus, Fhit loss-induced genome instability results in alterations in genes and gene expression associated with preneoplastic changes, a downstream consequence of TK1 inactivation, to promote neoplastic progression.Because deregulation of the Fhit-TK1 pathway results in changes in expression patterns promoting cellular transformation, we also investigated the mechanism of positive regulation of TK1 by Fhit. We demonstrate that loss of Fhit expression leads to decreased TK1 mRNA translation possibly due to accumulation of 5'-cap dinucleotides that can inhibit cap-dependent translation. Uncovering the mechanism by which Fhit regulates TK1 mRNA has important implications for understanding how Fhit modulates many cancer-associated processes through its function as a tumor suppressor and genome caretaker. Collectively, these findings support a model where deregulation of the Fhit-TK1 pathway initiates global genome instability in preneoplastic cells to promote cancer development. 2016-11-07 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1467385127 http://rave.ohiolink.edu/etdc/view?acc_num=osu1467385127 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Biology |
| spellingShingle |
Biology Karras, Jenna Fhit inactivation in neoplasia: <i>in vitro</i> insights into cancer initiation and progression |
| author |
Karras, Jenna |
| author_facet |
Karras, Jenna |
| author_sort |
Karras, Jenna |
| title |
Fhit inactivation in neoplasia: <i>in vitro</i> insights into cancer initiation and progression |
| title_short |
Fhit inactivation in neoplasia: <i>in vitro</i> insights into cancer initiation and progression |
| title_full |
Fhit inactivation in neoplasia: <i>in vitro</i> insights into cancer initiation and progression |
| title_fullStr |
Fhit inactivation in neoplasia: <i>in vitro</i> insights into cancer initiation and progression |
| title_full_unstemmed |
Fhit inactivation in neoplasia: <i>in vitro</i> insights into cancer initiation and progression |
| title_sort |
fhit inactivation in neoplasia: <i>in vitro</i> insights into cancer initiation and progression |
| publisher |
The Ohio State University / OhioLINK |
| publishDate |
2016 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=osu1467385127 |
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AT karrasjenna fhitinactivationinneoplasiaiinvitroiinsightsintocancerinitiationandprogression |
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1719440254624071680 |