Abstract
Oral Squamous Cell Carcinoma (OSCC) is the most common oral cancer worldwide. Treatments including surgery, radio- and chemo-therapies mostly result in debilitating side effects. Thus, a more accurate evaluation of patients at risk of recurrence after radio/chemo treatment is important for preserving their quality of life. We assessed whether the Telomeric Repeat-binding Factor 2 (TERF2) influences tumor aggressiveness and treatment response. TERF2 is over-expressed in many cancers but its correlation to patient outcome remains controversial in OSCC. Our retrospective study on sixty-two patients showed that TERF2 overexpression has a negative impact on survival time. TERF2-dependent survival time was independent of tumor size in a multivariate analysis. In vitro, TERF2 knockdown by RNA interference had no effect on cell proliferation, migration, senescence and apoptosis. Instead, TERF2 knockdown increased the expression of cytokines implicated in inflammation and angiogenesis, except for vascular endothelial growth factor. TERF2 knockdown resulted in a decrease vascularization and growth of xenograft tumors. Finally, response to erlotinib/Tarceva and cetuximab/Erbitux treatment was increased in TRF2 knocked-down cells. Hence, TERF2 may represent an independent marker of survival for OSCC and a predictive marker for cetuximab/Erbitux and erlotinib/Tarceva efficacy.
Highlights
Head and neck cancer is the fifth most common cancer in France and 90% of them are Oral Squamous Cell Carcinomas (OSCC)
We established a score of expression for Telomeric Repeat-binding Factor 2 (TERF2) inspired from HER2 evaluation in breast cancers to standardize TERF2 detection in OSCC (Figure 1)
A multivariate analysis showed that the TERF2 score (OR = 2.35 [1.01 – 5.45] 95% CI, P = 0.0424) was independent of tumor size (OR = 3.45 [1.387 – 8.628] 95% CI, P = 0.007) (Figure 2D) introducing a new biological prognostic marker of survival for OSCC
Summary
Head and neck cancer is the fifth most common cancer in France and 90% of them are Oral Squamous Cell Carcinomas (OSCC). Eighty percent of OSCCs are associated with over-expression and activation of the Epidermal Growth Factor Receptor (EGFR), Mitogen-Activated Protein Kinase (MAPK) and PI3 Kinase/AKT signaling pathways [2]. Telomeric Repeat Factor 2 (TERF2) is a component of the shelterin complex, which interacts with distal ends of chromosomes to protect them from being recognized as DNA double strand breaks by DNA damage repair systems [3]. TERF2 represents an essential link between telomeric DNA and other components of the shelterin complex. TERF2 loss of function leads to activation of DNA repair systems at telomeric loci, leading to cell www.impactjournals.com/oncotarget cycle arrest, senescence or cell death [4,5,6,7,8]. The link between TERF2 expression in tumor tissues, overall survival and treatment response remains unclear. The potential of TERF2 as a prognostic marker or a predictive marker of sensitivity/resistance to targeted therapies has not been studied
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