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Impact of RhoA overexpression on clinical outcomes in cervical squamous cell carcinoma treated with concurrent chemoradiotherapy.

ABSTRACT: The Rho-associated coiled-coil-containing protein kinase (ROCK) pathway is known to influence metastasis in several cancers; however, the impact of the pathway on clinical outcomes in patients undergoing radiotherapy remains unknown. In the present study, the expression of RhoA, RhoC, ROCK-1, ROCK-2 and p53 was immunohistochemically evaluated using biopsy specimens obtained from 49 patients with stage II-III cervical squamous cell carcinoma treated with concurrent chemoradiotherapy (CCRT). The relationship between the expression of these proteins and patient outcomes was investigated. RhoA overexpression was associated with significantly impaired disease-free survival and distant metastasis-free survival (P = 0.045 and P = 0.041, respectively) in stage III cancer patients. No differences in survival were observed based on the expression of the other proteins among stage III cancer patients. In stage II cancer patients, no differences in survival were noted based on the expression of any of the proteins. The expression of RhoA was able to successfully differentiate cervical cancer patients with distant metastasis after CCRT. This information may help stratify patients according to the risk of metastasis, thereby leading to the potential to provide individualized treatment.

SUBMITTER: Tanaka K

PROVIDER: S-EPMC7246076 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Impact of RhoA overexpression on clinical outcomes in cervical squamous cell carcinoma treated with concurrent chemoradiotherapy.

Tanaka Keiichi K Matsumoto Yoshitaka Y Ishikawa Hitoshi H Fukumitsu Nobuyoshi N Numajiri Haruko H Murofushi Keiko K Oshiro Yoshiko Y Okumura Toshiyuki T Satoh Toyomi T Sakurai Hideyuki H

Journal of radiation research 20200301 2

The Rho-associated coiled-coil-containing protein kinase (ROCK) pathway is known to influence metastasis in several cancers; however, the impact of the pathway on clinical outcomes in patients undergoing radiotherapy remains unknown. In the present study, the expression of RhoA, RhoC, ROCK-1, ROCK-2 and p53 was immunohistochemically evaluated using biopsy specimens obtained from 49 patients with stage II-III cervical squamous cell carcinoma treated with concurrent chemoradiotherapy (CCRT). The r ...[more]

PMID: 31976530

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Project description:BackgroundCervical squamous cell carcinoma (CSCC) is the main pathological type of cervical cancer, accounting for 80%-85% of cervical cancer. Owing to concurrent chemoradiotherapy (CCRT) resistance in a subset of CSCC patients, the treatment response is often unsatisfactory. Identifying predictors and therapeutic targets related to cisplatin-based CCRT resistance in CSCC is critical.MethodsWe reanalyzed GSE56363, an mRNA dataset from the GEO database with 21 patients with locally advanced CSCC, to identify differentially expressed genes (DEGs) related to CCRT resistance. The hub genes were screened from the protein-protein interaction network of DEGs using cytoHubba plug-in of Cytoscape software. Transcriptome sequencing technology was used to compare differential expression between SiHa cells overexpressing BRCA1 compared with control SiHa cells. Functional annotation for DEGs and gene set enrichment analysis (GSEA) was performed to identify DEG-enriched relative signaling pathways to examine the molecular mechanisms of BRCA1 in CCRT resistance of CSCC. qPCR was used to verify the expression of key genes in SiHa/DDP cells.ResultsA total of 609 DEGs including 223 upregulated DEGs and 386 downregulated DEGs were identified between the complete response to CCRT (CR) and noncomplete response to CCRT (NCR) CSCC patients based on the GSE56363 dataset. Ten hub genes with the highest degrees were identified via the plug-in CytoHubba in Cytoscape: BRCA1, CDCA8, ASPM, CDC45, RAD51, HMMR, CENPF, EXO1, DTL, and ZWINT genes, and BRCA1 ranked first. Through transcriptome sequencing analysis based on GSE141558, 1344 DEGs were identified in BRCA1-overexpressing SiHa cells, including 824 upregulated DEGs and 520 downregulated DEGs. GSEA results showed that CCRT-resistance related signaling pathways, such as the JAK/STAT signaling pathway and the WNT signaling pathway, were differentially enriched in BRCA1-expressing SiHa cells. STAT1, STAT2, and CCND1 were screened as the differentially expressed target genes of BRCA1 and may correlate with resistance of CSCC. qPCR results showed that only STAT1 was significantly increased in SiHa cells with GV230-BRCA1 plasmid transfection.ConclusionBRCA1 overexpression in SiHa cells may upregulate STAT1 to activate the JAK/STAT signaling pathway, suggesting a mechanism for enhanced CCRT resistance.

Project description:BackgroundTo investigate the magnetic resonance imaging (MRI)-based radiomics value in predicting the survival of patients with locally advanced cervical squamous cell cancer (LACSC) treated with concurrent chemoradiotherapy (CCRT).MethodsA total of 185 patients (training group: n = 128; testing group: n = 57) with LACSC treated with CCRT between January 2014 and December 2018 were retrospectively enrolled in this study. A total of 400 radiomics features were extracted from T2-weighted imaging, apparent diffusion coefficient map, arterial- and delayed-phase contrast-enhanced MRI. Univariate Cox regression and least absolute shrinkage and selection operator Cox regression was applied to select radiomics features and clinical characteristics that could independently predict progression-free survival (PFS) and overall survival (OS). The predictive capability of the prediction model was evaluated using Harrell's C-index. Nomograms and calibration curves were then generated. Survival curves were generated using the Kaplan-Meier method, and the log-rank test was used for comparison.ResultsThe radiomics score achieved significantly better predictive performance for the estimation of PFS (C-index, 0.764 for training and 0.762 for testing) and OS (C-index, 0.793 for training and 0.750 for testing), compared with the 2018 FIGO staging system (C-index for PFS, 0.657 for training and 0.677 for testing; C-index for OS, 0.665 for training and 0.633 for testing) and clinical-predicting model (C-index for PFS, 0.731 for training and 0.725 for testing; C-index for OS, 0.708 for training and 0.693 for testing) (P < 0.05). The combined model constructed with T stage, lymph node metastasis position, and radiomics score achieved the best performance for the estimation of PFS (C-index, 0.792 for training and 0.809 for testing) and OS (C-index, 0.822 for training and 0.785 for testing), which were significantly higher than those of the radiomics score (P < 0.05).ConclusionsThe MRI-based radiomics score could provide effective information in predicting the PFS and OS in patients with LACSC treated with CCRT. The combined model (including MRI-based radiomics score and clinical characteristics) showed the best prediction performance.

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Impact of RhoA overexpression on clinical outcomes in cervical squamous cell carcinoma treated with concurrent chemoradiotherapy.

Publications

Impact of RhoA overexpression on clinical outcomes in cervical squamous cell carcinoma treated with concurrent chemoradiotherapy.

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