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Astrocyte elevated ...
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Gnosa, Sebastian,1984-Linköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten
(författare)
Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response
Förlag, utgivningsår, omfång ...
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Linköping :Linköping University Electronic Press,2015
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84 s.
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electronicrdacarrier
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:liu-121868
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ISBN:9789176859704
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-121868URI
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https://doi.org/10.3384/diss.diva-121868DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:vet swepub-contenttype
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Ämneskategori:dok swepub-publicationtype
Serie
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Linköping University Medical Dissertations,0345-0082 ;1476
Anmärkningar
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The incidence and death rate for colorectal cancer (CRC) decreased during the last decades as a result of improved diagnosis and treatment. However, CRC is still the third most common cancer in the world, and is responsible for about 700 000 deaths per year worldwide. Therefore, it is important to understand the mechanisms of the disease, and to find molecular markers in order to further improve prognosis, and to develop new treatment strategies. Astrocyte elevated gene-1 (AEG-1), encoded by the MTDH gene, is upregulated in a variety of cancers. AEG-1 is involved in cell survival, proliferation, migration, invasion, metastasis, angiogenesis, and apoptosis.The aim of this thesis was to investigate the role of AEG-1 in CRC development and the impact of AEG-1 on the response of radiation treatment. The AEG-1 expression, analysed in different CRC patient cohorts in paper I and III, was increased in the tumour tissue compared with the normal mucosa, and higher in the lymph node and liver metastases. Expression analyses in normal and cancer cell lines confirmed these results. In paper II, sequencing of the complete coding sequence of the MTDH gene in 356 patients revealed 50 single nucleotide variants of which 29 were novel. Eight exonic variants were detected, including three frameshift variants which were probably pathogenic, and two missense variants located in functional protein regions. There was no correlation of the MTDH variants or AEG-1 expression with the patient survival. In paper III, we also investigated the impact of AEG-1 on the response to radiation treatment. AEG-1 knockdown decreased the cellular survival upon radiation in several colon cancer cell lines. The AEG-1 expression was furthermore analysed in patients, which were randomised to either surgery alone or preoperative radiotherapy (RT), followed by surgery. The rectal cancer patients with high AEG-1 expression treated with RT had a significantly higher risk of developing distant recurrence and had a worse disease free survival, likely due to the metastasis promoting properties of AEG-1. In paper IV, the impact of AEG-1 knockdown and radiation on migration and invasion was analysed in colon cancer cell lines in vitro and in a novel zebrafish model in vivo. AEG-1 knockdown decreased migration and invasion, and radiation-enhanced migration and invasion in the cell lines tested.In conclusion, our data suggest that AEG-1 is involved in CRC development, while MTDH gene variants probably not have a high clinical importance in CRC. Furthermore, AEG-1 is a promising radiosensitising target and a valuable prognostic marker in CRC. We further showed that AEG-1 knockdown inhibits migration and invasion, as well as radiation-enhanced cell migration and invasion.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Sun, Xiao-Feng,ProfessorLinköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,Region Östergötland, Onkologiska kliniken US(Swepub:liu)xiasu45
(preses)
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Starkhammar, Hans,Dr.Linköpings universitet,Avdelningen för kliniska vetenskaper,Medicinska fakulteten,Region Östergötland, Onkologiska kliniken US(Swepub:liu)hanst87
(preses)
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Zhang, Hong,Associate ProfessorSchool of Medicine, Örebro University, Örebro, Sweden(Swepub:liu)honzh78
(preses)
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Carstensen, John,ProfessorLinköpings universitet,Avdelningen för hälso- och sjukvårdsanalys,Medicinska fakulteten(Swepub:liu)johca98
(preses)
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Wiman, Klas,ProfessorDepartment of Oncology-Pathology, Karolinska institutet, Stockholm, Sweden
(opponent)
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Linköpings universitetAvdelningen för kliniska vetenskaper
(creator_code:org_t)
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