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Identification of Key Regulator Genes Linked to Radioresistance in Head and Neck Squamous Cell Carcinoma by Bioinformatic Processing of Transcript Data
Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery . Linköping University, Faculty of Health Sciences.
Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Central Hospital, University of Turku, Turku, Finland/Department of Medical Biochemistry, University of Turku, Turku, Finland.
Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institute, Stockholm, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Purpose: We analyzed basal expression patterns of cell lines with different intrinsic radiosensitivity to discover predictive markers of radiotherapy response.

Experimental Design: Five head and neck squamous cell carcinoma (HNSCC) cell lines were selected for microarray analysis. Two cell lines showed high resistance to radiation, two cell lines showed an intermediate resistance and one cell line was sensitive and therefore used as reference to other cell lines. Three gene lists were generated from this analysis; one list with commonly deregulated genes in all cell lines compared to the reference and two lists with deregulated genes for the intermediate and highly resistant cell lines compared to the reference, respectively. Gene Ontology enrichment profiling and Ingenuity Pathway Analysis was applied on all gene lists. Key transcript findings were verified at the protein level by Western blot.

Results: Expression analysis of the high and intermediate resistant cell lines compared to the reference resulted in approximately 1300 significantly altered transcripts, respectively; 552 transcripts were found commonly differently expressed. The deregulated transcripts enriched several GO-categories under biological process, cellular component and molecular function as well as multiple molecular networks in Ingenuity Pathway Analysis. A transcriptional profile of 28 key-regulator genes from the molecular networks was generated from the four resistant lines compared to the reference. Finally, immunoblot analysis supported deregulation at the protein level of markers implicated from the transcriptional-profile.

Conclusions: Novel markers for prediction of radiation sensitivity could be proposed from bioinformatic processing of gene-expression profiles in HNSCC carcinoma cells.

Keyword [en]
Microarray, Radiotherapy, Predictive biomarkers, Gene Ontology, Pathway analysis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-19570OAI: oai:DiVA.org:liu-19570DiVA: diva2:225482
Available from: 2009-06-29 Created: 2009-06-29 Last updated: 2010-01-14Bibliographically approved
In thesis
1. On Predictive Factors of Treatment Response in Head and Neck Squamous Cell Carcinoma
Open this publication in new window or tab >>On Predictive Factors of Treatment Response in Head and Neck Squamous Cell Carcinoma
2008 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer and yearly include 500 000 new cases worldwide. The outcomes for these patients have not been significantly improved over the last decades and the five year survival is still around 50 %. Establishing predictive markers of treatment response will have great impact on the clinical management of this disease.

The aim of this thesis was to elucidate markers of intrinsic response to radiotherapy and cisplatin. Combining expression patterns of 14 proteins and identifying mutations in the p53 gene, we were able to incorporate both protein and genetic changes to create a predictive model termed Number of Negative Points (NNP). We used the NNP model to statistically calculate the combination of factors that had the best correlation to intrinsic radiosensitivity (IR). We established that a panel of three markers, epidermal growth factor receptor (EGFR), survivin and splice site/missence mutations of p53, had the best correlation to IR (R=0.990, p<0.0001).

We also conducted gene expression analysis to investigate what genes and gene ontologies that are different between cell lines with varying IR. Furthermore, we wanted to identify key regulator genes with central positions of molecular networks, which were generated from the transcripts included in the deregulated gene ontologies. A transcriptional profile of 28 key regulator genes was generated. Immunoblot analysis supported deregulation at the protein level of three markers implicated from the transcriptional profile. We propose that these proteins, notch1, thrombospondin 1, and pai‐1 are predictive markers of IR.

Finally, on a subset of cell lines with sensitivity or resistance to cisplatin, we performed gene expression analysis. Markers of intrinsic cisplatin sensitivity (ICS) such as gene ontologies and key regulators of molecular networks were proposed and five genes, APOE, CTNNB1, MMP7, MMP13, and THBS1 were selected for further analysis. Quantitative polymerase chain reaction (qPCR) analysis of these genes in 25 cell lines established that MMP7 (p=0.0013) and MMP13 (p=0.058) are possible predictive markers of ICS.

The markers of IR and ICS presented here could, if confirmed in a clinical setting, guide clinicians in the choice of treatment and thus give a more individualized and effective therapy for patients with HNSCC.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. 37 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 90
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:liu:diva-17781 (URN)978-91-7393-736-8 (ISBN)
Presentation
(English)
Supervisors
Available from: 2009-06-29 Created: 2009-04-20 Last updated: 2009-09-15Bibliographically approved

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Jerhammar, FredrikRoberg, Karin

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Oto-Rhiono-Laryngology and Head & Neck Surgery Faculty of Health SciencesDepartment of ENT - Head and Neck Surgery UHL
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