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Radiosensitizing effect of THBS1 knockdown in radioresistant head and neck carcinoma cell lines

ABSTRACT: This study aimed to investigate the radiosensitizing effects of THBS1 knockdown in radioresistant head and neck squamous cell carcinoma (HNSCC) cell lines. Using siRNA-mediated silencing of THBS1 in CAL27 and Detroit 562 cells, we examined transcriptomic changes associated with enhanced sensitivity to proton beam irradiation. Bulk RNA-seq was performed to profile genome-wide expression patterns in control and THBS1-depleted cells, providing insights into gene expression programs linked to THBS1-mediated radioresistance and potential therapeutic targets.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305473 | GEO | 2025/08/21

REPOSITORIES: GEO

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Project description:Background: Radiotherapy plays an important role in the multimodal treatment of breast cancer. The response of a breast tumour to radiation depends not only on its innate radiosensitivity but also on tumour repopulation by cells that have developed radioresistance. Development of effective cancer treatments will require further molecular dissection of the processes that contribute to resistance. Methods: Radioresistant cell lines were established by exposing MDA-MB-231, MCF-7 and ZR-751 parental cells to increasing weekly doses of radiation. The development of radioresistance was evaluated through proliferation and colony formation assays. Phenotypic characterisation included migration and invasion assays and immunohistochemistry. Intrinsic differences and changes in response to radiation between parental and radioresistant cells were investigated by whole-transcriptome gene expression analysis. Gene enrichment and pathway-focused analyses identified signalling networks differentially activated in radioresistant cells, which were confirmed by western blotting. Results: Proliferation and colony formation assays confirmed radioresistance. Radioresistant cells exhibited enhanced migration and invasion, with evidence of epithelial-to-mesenchymal-transition, and limited activation of DNA damage and apoptotic pathways in response to 2 Gy ionising radiation. Significantly, acquisition of radioresistance in MCF-7 and ZR-751 cell lines resulted in a loss of expression of both ERα and PgR and an increase in EGFR expression; based on gene analysis they changed subtype classification from their parental luminal A to HER2-overexpressing (MCF-7 RR) and normal-like (ZR-751 RR) subtypes, indicating the extent of phenotypic changes and cellular plasticity involved in this process. Whole-transcriptome gene expression analysis identified down-regulation of ER signalling genes and up-regulation of genes associated with PI3K, MAPK and WNT pathway activity in radioresistant cell lines derived from ER+ cells; this was confirmed by western blot, which showed increased p-AKT and p-ERK expression following radiation. Conclusions: This is the first study to date that extensively describes the development and characterisation of three novel radioresistant breast cancer cell lines through both genetic and phenotypic analysis. More changes were identified between parental cells and their radioresistant derivatives in the ER+ (MCF-7 and ZR-751) compared with the ER- cell line (MDA-MB-231) model; however, multiple and likely interrelated mechanisms were identified that may contribute to the development of acquired resistance to radiotherapy.

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Radiosensitizing effect of THBS1 knockdown in radioresistant head and neck carcinoma cell lines

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