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Nuclear expression of WRAP53 beta is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma
Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
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2015 (English)In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 51, no 1, 24-30 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: Today there are no reliable predictive markers for radiotherapy response in head and neck squamous cell carcinoma (HNSCC), leading to both under-and over-treatment of patients, personal suffering, and negative socioeconomic effects. Inherited mutation in WRAP53 beta (WD40 encoding RNA Antisense to p53), a protein involved in intracellular trafficking, dramatically increases the risk of developing HNSCC. The purpose of this study was to investigate whether WRAP53 beta can predict response to radiotherapy in patients with HNSCC. Materials and methods: Tumor biopsies from patients with HNSCC classified as responders or non-responders to radiotherapy were examined for the expression of the WRAP53 beta protein and single nucleotide polymorphisms in the corresponding gene employing immunohistochemistry and allelic discrimination, respectively. In addition, the effect of RNAi-mediated downregulation of WRAP53 beta on the intrinsic radiosensitivity of two HNSCC cell lines was assed using crystal violet and clonogenic assays. Results: Nuclear expression of WRAP53 beta was significantly associated with better response to radiotherapy and improved patient survival. Downregulation of WRAP53 beta with siRNA in vitro enhanced cellular resistance to radiation. Conclusions: Our findings suggest that nuclear expression of WRAP53 beta promotes tumor cell death in response to radiotherapy and is a promising predictor of radiotherapy response in patients with HNSCC.

Place, publisher, year, edition, pages
Elsevier , 2015. Vol. 51, no 1, 24-30 p.
Keyword [en]
Head and neck cancer; Radiotherapy; Predictive factors; Survivin; WRAP53
National Category
Cancer and Oncology Otorhinolaryngology
Identifiers
URN: urn:nbn:se:liu:diva-113161DOI: 10.1016/j.oraloncology.2014.10.003ISI: 000346210900007PubMedID: 25456005OAI: oai:DiVA.org:liu-113161DiVA: diva2:780374
Note

Funding Agencies|Swedish Laryng Foundation; Ake Wiberg Foundation; Swedish Cancer Society [2008/552, 2010/545]; County Council of Ostergotland; Research Funds of Linkoping University Hospital

Available from: 2015-01-14 Created: 2015-01-12 Last updated: 2017-12-05
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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Garvin, StinaTiefenböck, KatharinaFarnebo, LovisaThunell, LenaRoberg, Karin

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Garvin, StinaTiefenböck, KatharinaFarnebo, LovisaThunell, LenaRoberg, Karin
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Department of Clinical Pathology and Clinical GeneticsDivision of Neuro and Inflammation ScienceFaculty of Medicine and Health SciencesDepartment of Otorhinolaryngology in LinköpingDivision of Cell BiologyFaculty of Health Sciences
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