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Forkhead box M1 regulates quiescence-associated radioresistance of human head and neck squamous carcinoma cells.

ABSTRACT: Cellular quiescence is a reversible growth arrest in which cells retain their ability to enter into and exit from the proliferative cycle. This study investigates the hypothesis that cell growth-state specific oxidative stress response regulates radiosensitivity of cancer cells. Results showed that quiescent (low proliferative index; >75% G1 phase and lower RNA content) Cal27 and FaDu human head and neck squamous cell carcinoma (HNSCC) are radioresistant compared to proliferating cells. Quiescent cells exhibited a three to tenfold increase in mRNA levels of Mn-superoxide dismutase (MnSOD), dual oxidase 2 (DUOX2) and dual-specificity phosphatase 1 (DUSP1), while mRNA levels of catalase (CAT), peroxiredoxin 3 (PRDX3) and C-C motif ligand 5 (CCL5) were approximately two to threefold lower compared to proliferating cells. mRNA levels of forkhead box M1 (FOXM1) showed the largest decrease in quiescent cells at approximately 18-fold. Surprisingly, radiation treatment resulted in a distinct gene expression pattern that is specific to proliferating and quiescent cells. Specifically, FOXM1 expression increased two to threefold in irradiated quiescent cells, while the same treatment had no net effect on FOXM1 mRNA expression in proliferating cells. RNA interference and pharmacological-based downregulation of FOXM1 abrogated radioresistance of quiescent cells. Furthermore, radioresistance of quiescent cells was associated with an increase in glucose consumption and expression of glucose-6-phosphate dehydrogenase (G6PD). Knockdown of FOXM1 resulted in a significant decrease in G6PD expression, and pharmacological-inhibition of G6PD sensitized quiescent cells to radiation. Taken together, these results suggest that targeting FOXM1 may overcome radioresistance of quiescent HNSCC.

SUBMITTER: Eckers JC

PROVIDER: S-EPMC4221113 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Forkhead box M1 regulates quiescence-associated radioresistance of human head and neck squamous carcinoma cells.

Eckers Jaimee C JC Kalen Amanda L AL Sarsour Ehab H EH Tompkins Van S VS Janz Siegfried S Son Jyung Mean JM Doskey Claire M CM Buettner Garry R GR Goswami Prabhat C PC

Radiation research 20140917 4

Cellular quiescence is a reversible growth arrest in which cells retain their ability to enter into and exit from the proliferative cycle. This study investigates the hypothesis that cell growth-state specific oxidative stress response regulates radiosensitivity of cancer cells. Results showed that quiescent (low proliferative index; >75% G1 phase and lower RNA content) Cal27 and FaDu human head and neck squamous cell carcinoma (HNSCC) are radioresistant compared to proliferating cells. Quiescen ...[more]

PMID: 25229973

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Project description:Radiotherapy is the primary means of treatment for patients with head and neck squamous cell carcinoma (HNSCC); however, radioresistance-induced recurrence is the primary cause of HNSCC treatment failure. Therefore, identifying specific predictive biomarkers of the response to radiotherapy may improve prognosis. In the present study, to identify the potential candidate genes associated with radioresistance in patients with HNSCC, the microarray datasets GSE9716, GSE61772 and GSE20549 were downloaded from the Gene Expression Omnibus database. The original CEL files were preprocessed using the Affymetrix package and quantile normalization and background correction were conducted using the Core package in Bioconductor. The GSE9716 dataset, consisting of 18 irradiated and 16 non-irradiated samples, was divided into two groups according to their exposure to irradiation: i) Non-irradiation group, which included 8 radioresistant samples and 8 radiosensitive samples; and ii) post-irradiation group, which included 9 radioresistant samples and 9 radiosensitive samples. The two groups were treated as separate datasets and screened. A total of 86 differentially expressed genes (DEGs) were identified in the non-irradiation group and 405 DEGs in the post-irradiation group. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis detected several significant functions associated with the DEGs. In the co-expression analysis, 76 hub genes in the light green module and 917 hub genes with a high connectivity were selected for further analysis. Finally, overlapping the DEGs and hub genes from the two groups yielded a map of 13 shared differentially expressed genes. The 13 genes showed significantly different expression in radioresistant samples compared with the radiosensitive samples before and after irradiation. Out of these genes, popeye domain-containing protein 3 (POPDC3) was highly expressed in the post-irradiation group compared with the non-irradiation group. In survival analysis, high POPDC3 expression correlated with poor a prognosis for patients with HNSCC. The independent prognostic factors were identified using univariate and multivariate Cox analyses based on The Cancer Genome Atlas database. These were incorporated into a nomogram to predict 3- and 5-year overall survival. Receiver operating characteristic curves were used to estimate the accuracy of the nomogram. Together these studies suggest that POPDC3 may serve as a potential predictive biomarker for prognosis and radioresistance of patients with HNSCC as well as clinical diagnosis and treatment of patients.

Dataset Information

Forkhead box M1 regulates quiescence-associated radioresistance of human head and neck squamous carcinoma cells.

Publications

Forkhead box M1 regulates quiescence-associated radioresistance of human head and neck squamous carcinoma cells.

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