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Strong expression of survivin is associated with positive response to radiotherapy and improved overall survival in head and neck squamous cell carcinoma patients
Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
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2013 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 133, no 8, 1994-2003 p.Article in journal (Refereed) Published
Abstract [en]

Head and neck squamous cell carcinoma (HNSCC) is a malignancy that is associated with severe mortality despite advances in therapy. Todays standard treatment most commonly includes radiotherapy, often combined with chemotherapy or surgery. There are so far no established biomarkers to predict response to radiation, and thus the aim of this study was to investigate a series of markers that could potentially identify HNSCC patients who would benefit from radiotherapy. The selected markers, both proteins (epidermal growth factor receptor, survivin and p53), and single nucleotide polymorphisms (SNPs) in the genes of XRCC3, XRCC1, XPC, XPD, MDM2, p53 and FGFR4 were correlated to the response to radiotherapy and overall survival. Investigations were performed on pretreatment tumor biopsies from patients classified as responders or nonresponders to radiotherapy. Protein expression was examined using immunohistochemistry and the genotyping of specific SNPs was analyzed using PCR-RFLP or pyrosequencing. We found that survivin expression was significantly stronger in the responder group (p = 0.003) and that patients with a strong survivin expression had a significantly better overall survival (p andlt; 0.001). Moreover, downregulation of survivin by siRNA in two HNSCC cell lines significantly decreased their sensitivity to radiation. Among the SNPs analyzed, patients with the XPD Lys751Gln SNP had a significantly shorter overall survival (p = 0.048), and patients with the FGFR4 Gly388Arg SNP had a significantly longer overall survival (p = 0.010). In conclusion, our results suggest that survivin plays an important role in the response to radiotherapy and may be a useful marker for predicting radiotherapy response in patients with HNSCC. less thanbrgreater than less thanbrgreater thanWhats new? Resistance to radiation therapy is a significant problem in the treatment of head and neck squamous cell carcinoma (HNSCC) and has created a need for the discovery of markers predictive of radiotherapy response. One promising marker is survivin, an inhibitor of apoptosis. Here, in pre-treatment biopsies from 40 patients with HNSCC, strong survivin expression was significantly associated with response to radiotherapy and increased overall survival. The data also indicate that single nucleotide polymorphisms in the genes XPD and FGFR4 are other possible predictors of overall survival after radiotherapy.

Place, publisher, year, edition, pages
Wiley-Blackwell , 2013. Vol. 133, no 8, 1994-2003 p.
Keyword [en]
head and neck tumors, radiotherapy, survivin, single nucleotide polymorphism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-97229DOI: 10.1002/ijc.28200ISI: 000322908600025OAI: oai:DiVA.org:liu-97229DiVA: diva2:646182
Note

Funding Agencies|Swedish Cancer Society|2008/5522010/545|Swedish Laryng Foundation||Foundation of Ake Wiberg||County Council of Ostergotland||Research Funds of Linkoping University Hospital||

Available from: 2013-09-06 Created: 2013-09-05 Last updated: 2017-12-06
In thesis
1. The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer
Open this publication in new window or tab >>The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Squamous cell carcinoma (SCC) is the most common histological type of cancer in the head and neck region and arises in the epithelial mucosa of the upper aerodigestive tract. Approximately one and a half million people are living with the diagnosis. Despite efforts in prevention and advances in treatment, the 5-year survival rate still lies around 60%, and recurrences and second primary tumors remain a problem. Moreover, treatment responses vary from patient to patient, highlighting the need for individually tailored treatments. To make this possible, biomarkers predicting treatment outcome are needed to better guide treatment decisions.

The aim of this thesis was to evaluate the expression of certain proteins and the frequency of certain SNPs (Single nucleotide polymorphisms) in tumor biopsies and cell cultures of head and neck squamous cell carcinomas (HNSCC), and to explore their potential as biomarkers for treatment outcome. Furthermore, we aimed to study the impact of hypoxia on treatment response, epithelial-tomesenchymal transition (EMT), and induction of cancer stem cells (CSC).

In papers I and II, we investigated two proteins, survivin and WRAP53β, using immunohistochemistry (IHC) in tumor biopsies from 40 patients categorized as Non-responders or Responders to radiotherapy. High expression of survivin and nuclear expression of WRAP53β were significantly more prevalent in the Responder group. The combination of these two factors correlated strongest to overall survival, but not to a significantly higher extent compared to survivin alone. Moreover, when examined separately, a high percentage of p53-stained cells and the presence of the SNP FGFR4 Gln388Arg correlated to improved overall survival, whereas the SNP XPD Lys751Gln was associated with worse overall survival. The latter three showed no significant correlations to radiotherapy response. In paper III, the two most promising proteins identified in papers I and II were analyzed in a study cohort of 149 tumor biopsies of glottic laryngeal SCC, categorized as T2N0-T3N0. In this patient group, no significant associations between survivin expression and survival could be found. However, expression of cytoplasmic WRAP53β was significantly linked to worse disease-free-survival (DSF) compared to nuclear WRAP53β or negative staining for WRAP53β. Positive expression of p16INK4a was found in 7% of the tumors. The prevalence of p16 INK4a was higher in younger patients (<60) and associated with absence of recurrence and longer DSF.

In paper IV, five HNSCC cell lines were cultured in normoxic (20% O2) and hypoxic (1% O2) conditions and changes in treatment response, EMT profile, and expression of CSC markers were examined. As expected, hypoxia induced EMT and to a certain extent expression of CSC markers. Silencing of the hypoxia-inducible-factor-1α (HIF-1α) only partly reversed these effects, suggesting that other mechanisms are involved. Whereas most cell lines became more resistant to treatment in hypoxia, one cell line (LK0412) became more sensitive to cetuximab-treatment in hypoxia, an effect that was revoked by depletion of HIF-1α, suggesting a possible sensitizing effect of HIF-1α to cetuximab-treatment.

Taken together, WRAP53β appears to be a promising biomarker candidate for treatment outcome in HNSCC, but further evaluation especially on the subcellular localization of WRAP53β is required. Even though the role of survivin in radiotherapy response in glottic SCC seems to be insignificant, it might have a more important role in other HNSCC subsites. As far as the effects of hypoxia, it appears that hypoxia might have a sensitizing effect on cetuximab-treatment in certain cases, which seems to be HIF1-α –dependent. Further studies are required to clarify the importance of this observation.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. 80 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1584
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-142112 (URN)10.3384/diss.diva-142112 (DOI)9789176854709 (ISBN)
Public defence
2017-11-16, Granitsalen, Norra Entrén, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Cancer SocietyRegion ÖstergötlandSwedish Research CouncilÅke Wiberg Foundation
Available from: 2017-10-23 Created: 2017-10-23 Last updated: 2017-11-14Bibliographically approved

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Farnebo, LovisaTiefenböck, KatharinaAnsell, AnnaThunell, LenaGarvin, StinaRoberg, Karin

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Farnebo, LovisaTiefenböck, KatharinaAnsell, AnnaThunell, LenaGarvin, StinaRoberg, Karin
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Oto-Rhiono-Laryngology and Head & Neck SurgeryFaculty of Health SciencesDepartment of Otorhinolaryngology in LinköpingDepartment of Clinical and Experimental MedicineDivision of NeuroscienceDivision of Cell BiologyOncology
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