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AEG-1 expression is an independent prognostic factor in rectal cancer patients with preoperative radiotherapy: a study in a Swedish clinical trial
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
University of Örebro, Sweden .
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för hälsa och samhälle. Linköpings universitet, Hälsouniversitetet.
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2014 (Engelska)Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 111, nr 1, s. 166-173Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND:

Preoperative radiotherapy (RT) is widely used to downstage rectal tumours, but the rate of recurrence varies significantly. Therefore, new biomarkers are needed for better treatment and prognosis. It has been shown that astrocyte elevated gene-1 (AEG-1) is a key mediator of migration, invasion, and treatment resistance. Our aim was to analyse the AEG-1 expression in relation to RT in rectal cancer patients and to test its radiosensitising properties.

METHODS:

The AEG-1 expression was examined by immunohistochemistry in 158 patients from the Swedish clinical trial of RT. Furthermore, we inhibited the AEG-1 expression by siRNA in five colon cancer cell lines and measured the survival after irradiation by colony-forming assay.

RESULTS:

The AEG-1 expression was increased in the primary tumours compared with the normal mucosa independently of the RT (P<0.01). High AEG-1 expression in the primary tumour of the patients treated with RT correlated independently with higher risk of distant recurrence (P=0.009) and worse disease-free survival (P=0.007). Downregulation of AEG-1 revealed a decreased survival after radiation in radioresistant colon cancer cell lines.

CONCLUSIONS:

The AEG-1 expression was independently related to distant recurrence and disease-free survival in rectal cancer patients with RT and could therefore be a marker to discriminate patients for distant relapse.

Ort, förlag, år, upplaga, sidor
Nature Publishing Group, 2014. Vol. 111, nr 1, s. 166-173
Nyckelord [en]
MTDH; astrocyte elevated gene-1; distant recurrence; disease-free survival
Nationell ämneskategori
Klinisk medicin Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
URN: urn:nbn:se:liu:diva-109376DOI: 10.1038/bjc.2014.250ISI: 000339163300020PubMedID: 24874474OAI: oai:DiVA.org:liu-109376DiVA, id: diva2:738055
Tillgänglig från: 2014-08-15 Skapad: 2014-08-15 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
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)
Opponent
Handledare
Tillgänglig från: 2015-10-12 Skapad: 2015-10-12 Senast uppdaterad: 2019-11-15Bibliografiskt granskad

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