Abstract
BackgroundAcquired and inherent radioresistance of tumor cells is related to tumor relapse and poor prognosis – not only in head and neck squamous cell carcinoma (HNSCC). The underlying molecular mechanisms are largely unknown. Therefore, systemic in-depth analyses are needed to identify key regulators of radioresistance. In the present study, subclones of the CAL-33 HNSCC cell line with different radiosensitivity were analyzed to identify signaling pathways related to the different phenotypes.MethodsSubclones with altered radiosensitivity were generated by fractionated irradiation of the parental CAL-33 cells. Differences in radiosensitivity were confirmed in colony formation assays. Selected subclones were characterized at the genomic and transcriptomic level by SKY, array CGH, and mRNA-microarray analyses. Time-course gene expression analyses upon irradiation using a natural cubic spline regression model identified temporally differentially expressed genes. Moreover, early and late responding genes were identified. Gene association networks were reconstructed using partial correlation. The Reactome pathway database was employed to conduct pathway enrichment analyses.ResultsThe characterization of two subclones with enhanced radiation resistance (RP) and enhanced radiosensitivity (SP) revealed distinct genomic and transcriptomic changes compared to the parental cells. Differentially expressed genes after irradiation shared by both subclones pointed to important pathways of the early and late radiation response, including senescence, apoptosis, DNA repair, Wnt, PI3K/AKT, and Rho GTPase signaling. The analysis of the most important nodes of the gene association networks revealed pathways specific to the radiation response in different phenotypes of radiosensitivity. Exemplarily, for the RP subclone the senescence-associated secretory phenotype (SASP) together with GPCR ligand binding were considered as crucial. Also, the expression of endogenous retrovirus ERV3-1in response to irradiation has been observed, and the related gene association networks have been identified.ConclusionsOur study presents comprehensive gene expression data of CAL-33 subclones with different radiation sensitivity. The resulting networks and pathways associated with the resistant phenotype are of special interest and include the SASP. The radiation-associated expression of ERV3-1 also appears highly attractive for further studies of the molecular mechanisms underlying acquired radioresistance. The identified pathways may represent key players of radioresistance, which could serve as potential targets for molecularly designed, therapeutical intervention.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0672-0) contains supplementary material, which is available to authorized users.
Highlights
Acquired and inherent radioresistance of tumor cells is related to tumor relapse and poor prognosis – in head and neck squamous cell carcinoma (HNSCC)
Expressed genes after irradiation shared by both subclones pointed to important pathways of the early and late radiation response, including senescence, apoptosis, DNA repair, Wnt, PI3K/AKT, and Rho GTPase signaling
The resulting networks and pathways associated with the resistant phenotype are of special interest and include the senescence-associated secretory phenotype (SASP)
Summary
Acquired and inherent radioresistance of tumor cells is related to tumor relapse and poor prognosis – in head and neck squamous cell carcinoma (HNSCC). Tumor cells derived from HNSCCs after radiotherapy have been reported to be more radioresistant than cell lines established prior to therapy, strengthening the clinical relevance of acquired radioresistance [8]. Along these lines, it was proposed that fractionated irradiation might preferentially eradicate radiosensitive cells, whereas radioresistant cells remain largely untouched. Different potential mechanisms of radioresistance have been proposed and extensively studied, the underlying molecular details remain largely unknown [9]. Systemic in-depth analyses are needed in order to identify the master regulators of acquired radioresistance, which could serve as potential biomarkers and future therapeutic targets in novel combined modality approaches
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