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AEG-1 knockdown in colon cancer cell lines inhibits radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background Radiotherapy is a well-established anti-cancer treatment. Although radiotherapy has been shown to significantly decrease the local relapse in rectal cancer patients, the rate of distant metastasis is still very high. Several studies have shown that radiation enhances migration and invasion both in vitro and in vivo. The aim of this study was to evaluate whether AEG-1 is involved in radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model.

Materials and Methods We evaluated the involvement of AEG-1 in migration and invasion and radiation-enhanced migration and invasion by Boyden chamber assay in three colon cancer cell lines and respective AEG-1 knockdown cell lines. Furthermore, we injected the cells in zebrafish embryos and evaluated the amount of disseminated cells into the tail.

Results Migration and invasion was decreased in all the AEG-1 knockdown cell lines. Furthermore, radiation enhanced migration and invasion, while AEG-1 knockdown could abolish this effect. The results from the zebrafish model confirmed the results obtained in vitro. MMP-9 secretion and expression were decreased in AEG-1 knockdown cells.

Conclusion Our results demonstrate that AEG-1 knockdown inhibits migration and invasion, as well as radiation-enhanced migration and invasion. We speculate that this is done via the downregulation of the intrinsic or radiation-enhanced MMP-9 expression. The zebrafish model can be used to study early events in radiation-enhanced invasion.

Keyword [en]
AEG-1, MTDH, LYRIC, Colon cancer, Zebrafish, Transwell migration and invasion, Radiation
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-121866OAI: oai:DiVA.org:liu-121866DiVA: diva2:860238
Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2015-10-12Bibliographically approved
In thesis
1. Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response
Open this publication in new window or tab >>Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 84 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1476
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:liu:diva-121868 (URN)10.3384/diss.diva-121868 (DOI)978-91-7685-970-4 (print) (ISBN)
Public defence
2015-11-13, Berzeliussalen, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2016-04-01Bibliographically approved

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