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Expression of AEG-1 mRNA and protein in colorectal cancer patients and colon cancer cell lines
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
Sichuan University, China.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
Skövde University, Sweden.
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2012 (Engelska)Ingår i: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 10, nr 109Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Astrocyte elevated gene 1 (AEG-1), an important oncogene, has been shown to be overexpressed in several types of cancers. In colorectal cancer (CRC), the protein level of AEG-1 is up-regulated in tumour tissue compared to normal mucosa, showing prognostic significance. Since little is known about the transcriptional level of AEG-1 expression and its biological pathway in CRC the aim of the present study was to examine the relationship of AEG-1 mRNA expression, the protein level and clinicopathological variables as well as its biology pathway in CRC. less thanbrgreater than less thanbrgreater thanMaterial and methods: The mRNA expression of AEG-1 was analysed by qPCR in fresh frozen patient samples including 156 primary tumours, along with the corresponding normal mucosa, and in five colon cancer cell lines, SW480, SW620, KM12C, KM12SM and KM12L4a. AEG-1 protein expression was investigated by immunohistochemistry in paraffin-embedded materials from 74 distant normal mucosa, 107 adjacent mucosa, 158 primary tumour, 35 lymph node metastasis and 9 liver metastasis samples. In addition, the AEG-1 protein expression was elucidated in the cell lines by Western blot. less thanbrgreater than less thanbrgreater thanResults: The lymph node metastatic cell line SW620 had a significantly higher AEG-1 mRNA (0.27 +/- 0.02) expression compared to the primary tumour cell line SW480 (0.17 +/- 0.04, p = 0.026). AEG-1 expression at the mRNA level and/or the protein level was significantly up-regulated gradually from normal mucosa to primary CRC, and then to lymph node metastasis and finally to liver metastasis (p andlt; 0.05). There were significant associations of AEG-1 mRNA expression with tumour location (p = 0.047), as well as mRNA and protein expression with the tumour stage (p andlt; 0.03). Furthermore AEG-1 protein expression was positively related to biological variables including NF-kappa B, p73, Rad50 and apoptosis (p andlt; 0.05). less thanbrgreater than less thanbrgreater thanConclusion: AEG-1 is up-regulated, at the mRNA and the protein level, during CRC development and aggressiveness, and is related to tumour location and stage. It may play its role in CRC through the NF-kappa B signaling pathway.

Ort, förlag, år, upplaga, sidor
BioMed Central , 2012. Vol. 10, nr 109
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-80795DOI: 10.1186/1479-5876-10-109ISI: 000307018200001OAI: oai:DiVA.org:liu-80795DiVA, id: diva2:548230
Anmärkning

Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||Health Research Council in the South-East of Sweden||

Tillgänglig från: 2012-08-30 Skapad: 2012-08-30 Senast uppdaterad: 2018-10-08
Ingår i avhandling
1. Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response
Öppna denna publikation i ny flik eller fönster >>Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2015. s. 84
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1476
Nationell ämneskategori
Cancer och onkologi Radiologi och bildbehandling
Identifikatorer
urn:nbn:se:liu:diva-121868 (URN)10.3384/diss.diva-121868 (DOI)978-91-7685-970-4 (ISBN)
Disputation
2015-11-13, Berzeliussalen, Campus US, Linköping, 13:00 (Engelska)
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Handledare
Tillgänglig från: 2015-10-12 Skapad: 2015-10-12 Senast uppdaterad: 2019-11-15Bibliografiskt granskad

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Gnosa, SebastianWang, Chao-JieStratmann, JohannesSun, Xiao-FengArbman, Gunnar

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