In the past, we applied global gene expression profiling on matched samples of primary and recurrent tumors of an orthotopic squamous cell carcinoma model in mice to identify differentially expressed genes [4]. One candidate gene with an increased transcript level in recurrent as compared to primary tumors encoded for the mouse homologue of human submaxillary gland androgen-regulated protein 3A (SMR3A), which belongs to the opiorphin gene family [5]. More recently, SMR3A expression was detected in a subgroup of patients with primary oropharyngeal squamous cell carcinoma (OPSCC) and served as an independent risk factor for unfavorable prognosis [6]. However, the regulation of SMR3A and its putative mode of action in the pathogenesis of HNSCC or in response to treatment have not been addressed, so far.
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In this study, we unraveled prominent SMR3A expression in vital tumor cells upon fractionated IR. Although ectopic SMR3A expression had no significant impact on tumor-relevant processes under normal growth conditions in vitro, presented data provide compelling experimental evidence that it might serve as a surrogate marker for a subpopulation of resistant cells as a putative source for tumor relapse after radiotherapy. In line with this assumption, a previous retrospective study unraveled high SMR3A expression as a risk factor for unfavorable progression-free and overall survival in a cohort of OPSCC patients [6].
In contrast to ESR1, ESR2 is usually described as a tumor suppressor in estrogen-sensitive malignancies [24]. However, we detected a positive staining for ESR2 expression as a common event in OPSCC, while ESR1-positive tumor cells were a rather rare event (data not shown). In line with our hypothesis that SMR3A serves as a surrogate marker for active ESR2 signaling and predicts treatment resistance, the combined expression of both proteins was associated with an unfavorable clinical outcome concerning progression-free and disease-specific survival after definitive or adjuvant radiotherapy. Although multivariable Cox proportional hazard regression models supported the assumption that ESR2 and SMR3A staining patterns are associated with clinical outcome, our retrospective study is limited by the low amount of patients for distinct subgroups. A major challenge for the future will be the analysis of ESR2 and SMR3A but also other downstream targets in larger cohort studies, including specimens from HNSCC of other locations. 2ff7e9595c
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