Regulation of submaxillary gland androgen-regulated protein 3A via estrogen receptor 2 in radioresistant head and neck squamous cell carcinoma cells

Abstract

BackgroundMolecular mechanisms of intrinsic or acquired radioresistance serve as critical barrier for curative therapy of head and neck squamous cell carcinoma (HNSCC) and remain a major obstacle for progression-free and disease-specific survival.MethodsHNSCC cell lines were treated with a protocol of fractionated irradiation (IR, 4× 2Gy) alone or in combination with antagonists of estrogen receptor signaling and viability was determined by a colony-forming assay (CFA). Expression of submaxillary gland androgen-regulated protein 3A (SMR3A) and estrogen receptor 2 (ESR2) were assessed in tumor cells in vitro by RQ-PCR, Western blot analysis and immunofluorescence staining, and by immunohistochemical staining of tissue microarrays containing tumor sections from patients with oropharyngeal squamous cell carcinoma (OPSCC), which were treated by definitive or adjuvant radiotherapy. Subgroups with distinct SMR3A and ESR2 expression patterns were correlated with clinical parameters and survival outcome including multivariable analysis.ResultsFractionated irradiation (IR) revealed an accumulation of tumor cells with prominent SMR3A expression, which was accompanied by an up-regulation of the estrogen receptor 2 (ESR2). ESR2-dependent regulation of SMR3A was supported by induced expression after stimulation with estradiol (E2), which was impaired by co-treatment with 4-Hydroxytamoxifen (TAM) or Fulvestrant, respectively. Both drugs significantly sensitized FaDu cells to fractionated IR as determined by a CFA and accelerated apoptosis. These data suggest a critical role of ESR2 in radioresistance and that SMR3A might serve as a surrogate marker for active ESR2 signaling. In line with this assumption, ESR2-positive oropharyngeal squamous cell carcinoma (OPSCC) with high SMR3A expression had an unfavorable progression-free and disease-specific survival as compared to those tumors with low SMR3A expression.ConclusionsIn summary, our findings provide compelling experimental evidence that HNSCC with SMR3A and ESR2 co-expression have a higher risk for treatment failure and these patients might benefit from clinically well-established drugs targeting estrogen receptor signaling.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0496-2) contains supplementary material, which is available to authorized users.

Variable Retention of Differentiation-specific DNA Replication Timing in Human Pediatric Leukemia

“…RT signature #1 contained features that were early replicating in the cells from the CNS relapse samples but late in all other TCF3-PBX1-positive BCP-ALL patients. Gene ontology (GO) analysis of these chromosomal segments indicated that genes within this signature are associated 220 with neurological regulation (Figure 5E); specifically, this ontology term is linked to genes from the opiorphin family (SMR3A, SMR3B and OPRPN) which are up-regulated in head and neck squamous cell carcinoma (HNSCC) (Grünow et al, 2017). Additionally, odontogenesis regulation was also associated with this RT signature, derived from genes AMBN, AMTN, ODAM, ENAM, which are evolutionarily related genes all located within 500 kb of each other on chro-225 mosome 4 (Sire et al, 2007).…”

Estrogen Receptor Signaling in Radiotherapy: From Molecular Mechanisms to Clinical Studies

“…Apart from that single case, no study has been published for other cancer entities that used concurrent radiotherapy and anti-hormonal therapy. Recently, a preclinical study conducted in our group provided experimental evidence for a causal link between ERβ expression and radioresistance in head and neck cancer [ 95 ].…”

Investigating the role of opiorphin genes in prostate cancer and the possible genetic mechanisms by which they modulate tumor growth and androgen-sensitivity.

“…This has been supported by several recent reports associating dysregulated expression opiorphin-encoding genes with cancer. Upregulated ProL1 expression was observed in invasive multifocal/multicentric compared to unifocal breast cancer [23] and increased hSMR3A expression was associated with unfavorable survival outcomes following surgery for oropharyngeal squamous cell carcinoma [24,25]. In addition, in a meta-analysis using a rank aggregation approach to identify changes in gene expression in common between different cancer types, ProL1 was included in the aggregated list of top-50 genes [26].…”