Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma

Jerhammar, Fredrik; Ceder, Rebecca; Garvin, Stina; Grénman, Reidar; Grafström, Roland C.; Roberg, Karin

doi:10.4161/cbt.10.12.13432

Cited by 67 publications

(50 citation statements)

References 39 publications

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“…Decreased sensitivity to treatment with cetuximab, cisplatin, and radiation in hypoxic UT-SCC-2 and UT-SCC-14 cells has been attributed to gain of a mesenchymal phenotype. These findings are supported by a study of Holz et al (131) that also showed decreased radiosensitivity in HNSCC cells with a mesenchymal phenotype, and is in agreement with our previous findings that the mesenchymal marker FN1 is upregulated in radioresistant cells (50).…”

Section: The Impact Of Hypoxia On Hnscc Cell Linessupporting

confidence: 82%

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

Tiefenböck-Hansson¹

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v ABSTRACTSquamous 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-to-mesenchymal 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 Nonresponders 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 ABSTRACT vi 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% O 2 ) and hypoxic (1% O 2 )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) ...

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Section: The Impact Of Hypoxia On Hnscc Cell Linessupporting

confidence: 82%

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

Tiefenböck-Hansson¹

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“…Fibronectin is also a candidate biomarker for several solid tumor types, including ovarian, prostate and breast cancer (1,2). In addition to its implication in cancer development, fibronectin also acts as a potential biomarker for treatment-associated resistance (5).…”

Section: Introductionmentioning

confidence: 99%

“…Altered expression of fibronectin, degradation and organization have been associated with a number of pathologies, including cancer (1)(2)(3)(4)(5)(6)(7)(8). Several of the morphological changes observed in tumor types and tumor-derived cell lines have been attributed to decreased expression of fibronectin, increased fibronectin degradation, and/or decreased expression of fibronectin-binding receptors, including α5β1 integrins (1)(2)(3)(4)(5)(6)(7)(8). Fibronectin is also a candidate biomarker for several solid tumor types, including ovarian, prostate and breast cancer (1,2).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Fibronectin serves a prominent role in cell adhesion, growth, migration and differentiation, and it is important for processes, including wound healing and embryonic development via integrins and other cell surface receptors (1)(2)(3)(4)(5)(6)(7)(8). Altered expression of fibronectin, degradation and organization have been associated with a number of pathologies, including cancer (1)(2)(3)(4)(5)(6)(7)(8). Several of the morphological changes observed in tumor types and tumor-derived cell lines have been attributed to decreased expression of fibronectin, increased fibronectin degradation, and/or decreased expression of fibronectin-binding receptors, including α5β1 integrins (1)(2)(3)(4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

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Levels of serum fibronectin as a biomarker in gastric cancer patients: Correlation with clinical diagnosis and outcome

Taş

Bilgin

Karabulut

et al. 2016

Molecular and Clinical Oncology

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Abstract.Fibronectin is an important component of the extracellular matrix and serves a role in the pathogenesis of multiple malignancies. The expression of fibronectin also affects the outcome for patients with cancer. The objective of the present study was to determine the clinical significance of the serum fibronectin levels in patients with gastric cancer. A total of 63 patients with a pathologically confirmed diagnosis of gastric cancer were enrolled into the present study. Serum fibronectin concentrations were determined by the solid-phase sandwich enzyme-linked immunosorbent assay method. Age and sex matched healthy controls (n=30) were included in the analysis. The median age at diagnosis was 62 years (range 28-82 years). The baseline serum fibronectin levels of the patients with gastric cancer were significantly higher compared with those in the control group (median values, 606, vs. 193 ng/ml; P<0.001). The known clinical variables, including the age of the patient, gender, site of lesion, histology, histological grade, stage of disease and serum tumor markers, including lactate dehydrogenase, carcinoembryonic antigen and cancer antigen 19.9, were not found to be correlated with serum fibronectin concentrations (P>0.05). In addition, no correlation was observed in serum fibronectin level and response to chemotherapy (P=0.12). Serum fibronectin concentration demonstrated no prognostic role on survival (P=0.43). In conclusion, the serum levels of fibronectin may have a good diagnostic marker in patients with gastric cancer. However, its predictive and prognostic values remain to be elucidated.

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A three‐gene signature from protein–protein interaction network of LOXL2‐ and actin‐related proteins for esophageal squamous cell carcinoma prognosis

et al. 2017

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Current staging is inadequate for predicting clinical outcome of esophageal squamous cell carcinoma (ESCC). Aberrant expression of LOXL2 and actin‐related proteins plays important roles in ESCC. Here, we aimed to develop a novel molecular signature that exceeds the power of the current staging system in predicting ESCC prognosis. We found that LOXL2 colocalized with filamentous actin in ESCC cells, and gene set enrichment analysis (GSEA) showed that LOXL2 is related to the actin cytoskeleton. An ESCC‐specific protein–protein interaction (PPI) network involving LOXL2 and actin‐related proteins was generated based on genome‐wide RNA‐seq in 15 paired ESCC samples, and the prognostic significance of 14 core genes was analyzed. Using risk score calculation, a three‐gene signature comprising LOXL2,CDH1, and FN1 was derived from transcriptome data of patients with ESCC. The high‐risk three‐gene signature strongly correlated with poor prognosis in a training cohort of 60 patients (P = 0.003). In mRNA and protein levels, the prognostic values of this signature were further validated in 243 patients from a testing cohort (P = 0.001) and two validation cohorts (P = 0.021, P = 0.007). Furthermore, Cox regression analysis revealed that the signature was an independent prognostic factor. Compared with using the signature or TNM stage alone, the combined model significantly enhanced the accuracy in evaluating ESCC prognosis. In conclusion, our data reveal that the tumor‐promoting role of LOXL2 in ESCC is mediated by perturbing the architecture of actin cytoskeleton through its PPIs. We generated a novel three‐gene signature (PPI interfaces) that robustly predicts poor clinical outcome in ESCC patients.

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Fibronectin 1 is a potential biomarker for radioresistance in head and neck squamous cell carcinoma

Cited by 67 publications

References 39 publications

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

Levels of serum fibronectin as a biomarker in gastric cancer patients: Correlation with clinical diagnosis and outcome

A three‐gene signature from protein–protein interaction network of LOXL2‐ and actin‐related proteins for esophageal squamous cell carcinoma prognosis

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