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Matrix metalloproteinase-7 and -13 predict response to cisplatin in head and neck cancer
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Oto-Rhino-Laryngologi. Linköpings universitet, Hälsouniversitetet.
Institute of Environmental Medicine, Division of Biochemical Toxicology and Experimental Cancer Research, Karolinska Institution, Stockholm, Sweden.
Department of Otorhinolaryngology, Head & Neck Surgery, Turku University Central Hospital, Finland.
Vise andre og tillknytning
(engelsk)Manuskript (Annet vitenskapelig)
Abstract [en]

Purpose: To identify gene ontology categories and key regulators with impact on the intrinsic cisplatin sensitivity (ICS) in head and neck squamous cell carcinoma (HNSCC).

Experimental design: The ICS was determined in 35 HNSCC cell lines. Three of these cell lines, one sensitive and two resistant, were selected for microarray analysis. Gene Ontology (GO) categories were assessed using the gene ontology tree machine (GOTM) tool, and transcripts included in these categories were further analyzed using Ingenuity Pathway Analysis (IPA) for detection of key regulator genes. A group of key regulators were verified at protein level by Western blot analysis and on mRNA level using quantitative real-time PCR (qPCR).

Results: 781 transcripts were detected as significantly differently expressed for the resistant cell lines compared to the sensitive cell line. A total of ten different categories were enriched in GOTM by these transcripts and a transcriptional profile was made from the 20 key regulators identified in the IPA analysis. Five key regulator genes, apolipoprotein E (APOE), catenin beta1 (CTNNB1), matrix metalloproteinase-7 (MMP-7), matrix metalloproteinase-13 (MMP-13), and thrombospondin 1 (THBS1), were verified in 25 HNSCC cell lines on mRNA level using qPCR. The results confirmed MMP-7 (p=0.0013) and implied MMP-13 (p=0.058) as potential biomarkers of ICS.

Conclusions: We conclude that genome-wide transcriptional analysis and appropriate bioinformatics enable the identification of genes with impact on treatment response. Furthermore, we propose MMP-7 and MMP-13 as predictive markers of cisplatin resistance in HNSCC.

Emneord [en]
Predictive markers, chemotherapy, microarray and intrinsic cisplatin resistance
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-19571OAI: oai:DiVA.org:liu-19571DiVA, id: diva2:225483
Tilgjengelig fra: 2009-06-29 Laget: 2009-06-29 Sist oppdatert: 2010-01-14bibliografisk kontrollert
Inngår i avhandling
1. On Predictive Factors of Treatment Response in Head and Neck Squamous Cell Carcinoma
Åpne denne publikasjonen i ny fane eller vindu >>On Predictive Factors of Treatment Response in Head and Neck Squamous Cell Carcinoma
2008 (engelsk)Licentiatavhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2008. s. 37
Serie
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 90
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-17781 (URN)978-91-7393-736-8 (ISBN)
Presentation
(engelsk)
Veileder
Tilgjengelig fra: 2009-06-29 Laget: 2009-04-20 Sist oppdatert: 2009-09-15bibliografisk kontrollert

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