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Targeting FBXO22 enhances radiosensitivity of non-small cell lung cancer by inhibiting FOXM1/Rad51 axis

ABSTRACT: FBXO22 is the substrate recognition subunit of SCF E3 ubiquitin ligase, which plays an important role in the occurrence, development and therapeutic response of solid tumors.At present, the relationship between FBXO22 and radiosensitivity of lung cancer has not been fully elucidated.Here we present evidence to prove that abnormally expressed FBXO22 in lung cancer promotes transcriptional activation of homologous recombination enzyme Rad51 by up-regulating transcription factor FOXM1, which in turn induces radioresistance in lung cancer.By comparing with the reference data set of cMap database, Deguelin was identified as a small molecular inhibitor of FBXO22.Deguelin increases the radiosensitivity of lung cancer cells in vitro and in vivo in a FBXO22-dependent manner and is safely tolerated.This study revealed the identity of a novel radioresistance biomarker of FBXO22 and provided preclinical evidence for the clinical transformation of this target by screening small molecular inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235374 | GEO | 2024/02/07

REPOSITORIES: GEO

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Project description:Purpose: Predominant causes of head and neck cancer recurrence after radiotherapy are rapid repopulation, hypoxia, fraction of cancer stem cells and intrinsic radioresistance. Currently, intrinsic radioresistance can only be assessed by ex-vivo colony assays. Besides being time-consuming, colony assays do not identify causes of intrinsic resistance. We aimed to identify a biomarker for intrinsic radioresistance to be used before start of treatment and to reveal biological processes that could be targeted to overcome intrinsic resistance. Experimental design: We analyzed both micro- and messenger RNA expression in a large panel of HNSCC cell lines. Expression was measured on both irradiated and unirradiated samples. Results were validated using modified cell lines and a series of laryngeal cancer patients. Results: MiRs, mRNAs and gene sets that correlated with resistance could be identified from expression data of unirradiated cells. The presence of epithelial to mesenchymal transition (EMT) and low expression of miRs involved in the inhibition of EMT were important radioresistance determinants. This finding was validated in two independent cell line pairs, in which the induction of EMT reduced radiosensitivity. Moreover, low expression of the most important miR (miR-203) was shown to correlate with local disease recurrence after radiotherapy in a series of laryngeal cancer patients. Conclusions: These findings indicate that EMT and low expression of EMT-inhibiting miRs, especially miR-203, measured in pre-treatment material, causes intrinsic radioresistance of HNSCC, which could enable identification and treatment modification of radioresistant tumors. Matched pairs of pre-treatment biopsies of 34 patients treated at The Netherlands Cancer Institute between 2002 and 2010. Patients with T2-3 laryngeal cancers, all treated with radiotherapy alone with a curative intent. The series was designed to be a matched cohort of 17 patients with local recurrences matched with 17 local cures. There were no significant differences between groups with and without local recurrence in age, gender, subsite, T-stage or treatment year.

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Targeting FBXO22 enhances radiosensitivity of non-small cell lung cancer by inhibiting FOXM1/Rad51 axis

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