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Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation.

ABSTRACT: Although numerous studies have used systemic approaches to identify prognostic predictors in oral squamous cell carcinoma (OSCC), the effectiveness of these approaches has not been assessed clinically. Further, the mechanism underlying malignant behaviors in OSCC is poorly characterized. This study aimed to develop and verify accurate prognostic predictors for OSCC patients and assess the associated biology. We identified an OSCC-recurrence-related gene signature (ORGS) using a Cox regression analysis. Functional enrichment analysis was used to identify enriched pathways and biological processes to reveal the underlying mechanism of OSCC malignant behavior. The ORGS successfully divided OSCC patients into low- and high-risk groups with significantly different overall survivals. Pathway analysis revealed oxidative phosphorylation (OXPHOS) as a signaling pathway associated with the ORGS in OSCC. Interestingly, high OXPHOS status was strongly associated with poor overall survival in OSCC patients. Mediator complex subunit 30 (MED30) was a predicted upstream regulator of OXPHOS, and knockdown of MED30 reduced histone acetylation. We identified that the ORGS was strongly correlated with OXPHOS regulatory processes, suggesting OXPHOS as a key mechanism leading to poor prognosis in OSCC.

SUBMITTER: Noh JK

PROVIDER: S-EPMC9812830 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation.

Noh Joo Kyung JK Woo Seon Rang SR Kong Moonkyoo M Lee Min Kyeong MK Lee Jung Woo JW Lee Young Chan YC Ko Seong-Gyu SG Eun Young-Gyu YG

Molecular oncology 20221123 1

Although numerous studies have used systemic approaches to identify prognostic predictors in oral squamous cell carcinoma (OSCC), the effectiveness of these approaches has not been assessed clinically. Further, the mechanism underlying malignant behaviors in OSCC is poorly characterized. This study aimed to develop and verify accurate prognostic predictors for OSCC patients and assess the associated biology. We identified an OSCC-recurrence-related gene signature (ORGS) using a Cox regression an ...[more]

PMID: 36271693

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Project description:BackgroundGlucose metabolism in cancer associated fibroblasts (CAFs) within the tumor microenvironment is a material and energy source for tumorigenesis and tumor development. However, the characteristics and important regulatory mechanisms of glucose metabolism in fibroblasts associated with oral squamous cell carcinoma (OSCC) are still unknown.MethodsWe successfully isolated, cultured, purified and identified CAFs and normal fibroblasts (NFs). Cell culture, immunohistochemistry (IHC) and CCK8, flow cytometry, Seahorse XF Analyzer, MitoTracker assay, western blotting (WB), transmission electron microscope, Quantitative real-time PCR (qPCR), immunofluorescence (IF), and Label-free quantitative proteomics assay, animal xenograft model studies and statistical analysis were applied in this study.ResultsWe demonstrated that the proliferation activity of CAFs was significantly enhanced as compared to NFs, while the apoptosis rate was significantly decreased. CAFs in OSCC preferentially use oxidative phosphorylation (OXPHOS) rather than glycolysis. Moreover, CAFs showed stronger maximal respiration, a larger substantial mitochondrial spare respiratory capacity (SRC) and higher adenosine triphosphate (ATP) production capacity than NFs. The results of mitotracker green fluorescence staining showed that compared with NFs, CAFs exhibited stronger green fluorescence. The results of WB showed the expression level of Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) obviously increased in CAFs compared to NFs. These results confirmed that CAFs have greater mitochondrial activity and function than NFs. Furthermore, Label-free quantitative proteomics assays showed that both ATP synthase subunit O (ATP5O) and tumor necrosis factor receptor-associated protein 1 (TRAP1) are important differentially expressed proteins in the mitochondria of CAFs/NFs. Overexpression of TRAP1 in CAFs increased basal oxygen consumption rate (OCR), maximal respiration, ATP production and SRC. In vivo, overexpression TRAP1 expression in CAFs suppress tumor growth.ConclusionTaken together, the results indicated that TRAP1 is an important regulatory molecule of CAFs glucose metabolism and promotes OSCC progression by regulating the OXPHOS of CAFs.

Project description:Simple Summary Here, we examined the presence and clinical relevance of A20 in oral squamous cell carcinoma (OSCC). Using a tissue microarray (TMA), immunohistochemical A20 expression as well as tumor-infiltrating lymphocytes (TIL) were analyzed. Hereby, A20 expression was significantly increased in TILs and patients with elevated A20 expression in stromal CD3+ cells showed ameliorated survival in uni- as well as multivariable analyses. Abstract A20, known as a potent inhibitor of NF-κB signaling, has been characterized in numerous clinical as well as preclinical studies. Recently, especially in various malignant diseases, the prognostic and therapeutic relevance of A20 was investigated. In oral squamous cell carcinoma (OSCC) however, the characterization of A20 is uncharted territory. We analyzed a tissue microarray (TMA) of 229 surgically-treated OSCC patients (2003–2013). Immunohistochemical (IHC) stainings were performed for A20 and CD3; additionally, standard haematoxylin-eosin staining was applied. IHC findings were correlated with a comprehensive dataset, comprising clinical and pathohistological information. A20 expression was analyzed in tumor cells as well as in tumor infiltrating lymphocytes (TILs) and correlated with the overall survival (OS) and recurrence-free survival (RFS) using uni- and multivariable Cox regression. The median follow-up time was 10.9 years and the A20 expression was significantly decreased in CD3+ TILs compared to mucosa-infiltrating lymphocytes (MILs). In the Kaplan–Meier analyses, higher A20 expression in TILs was correlated with better OS (p = 0.017) and RFS (p = 0.020). In the multivariable survival analysis, A20 overexpression correlated with improved OS (HR: 0.582; 95% CI 0.388–0.873, p = 0.009) and RFS (HR 0.605; 95% CI 0.411–0.889, p = 0.011). Our results indicate a novel prognostic role for A20 in OSCC. Due to its elevated expression in TILs, further research is highly desirable, which therefore could offer new therapeutic opportunities for patients suffering from OSCC.

Project description:BackgroundAutophagy, a highly conserved self-digesting process, has been deeply involved in the development and progression of oral squamous cell carcinoma (OSCC). However, the prognostic value of autophagy-related genes (ARGs) for OSCC still remains unclear. Our study set out to develop a multigene expression signature based on ARGs for individualized prognosis assessment in OSCC patients.MethodsBased on The Cancer Genome Atlas (TCGA) database, we identified prognosis-related ARGs through univariate COX regression analysis. Then we performed the least absolute shrinkage and selection operator (LASSO) regression analysis to identify an optimal autophagy-related multigene signature with the subsequent validation in testing set, GSE41613 and GSE42743 datasets.ResultsWe identified 36 prognosis-related ARGs for OSCC. Subsequently, the multigene signature based on 13 prognostic ARGs was constructed and successfully divided OSCC patients into low and high-risk groups with significantly different overall survival in TCGA training set (p < 0.0001). The autophagy signature remained as an independent prognostic factor for OSCC in univariate and multivariate Cox regression analyses. The area under the curve (AUC) values of the receiver operating characteristic (ROC) curves for 1, 3, and 5-year survival were 0.758, 0.810, 0.798, respectively. Then the gene signature was validated in TCGA testing set, GSE41613 and GSE42743 datasets. Moreover, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and single-sample gene set enrichment analysis (ssGSEA) revealed the underlying biological characteristics and signaling pathways associated with this signature in OSCC. Finally, we constructed a nomogram by combining the gene signature with multiple clinical parameters (age, gender, TNM-stage, tobacco, and alcohol history). The concordance index (C-index) and calibration plots demonstrated favorable predictive performance of our nomogram.ConclusionIn summary, we identified and verified a 13-ARGs prognostic signature and nomogram, which provide individualized prognosis evaluation and show insight for potential therapeutic targets for OSCC.

Project description:The aim of this study is to provide an extended, retrospective validation of a previously described 4-gene signature (MMP1, COL4A1, P4HA2, and THBS2) predictive of oral carcinoma recurrence. We assessed an independent cohort including 245 histologically normal surgical margins from 62 patients with OSCC. Gene expression was determined using a color-coded probe assay for quantitative gene expression analysis. All margins and tumor blocks were cut (4-5µm tick) and stained with Hematoxylin-Eosin and tissues were subjected to needle microdissection using the stereo microscope Leica EZ4 (Leica Microsystems, Wetzlar, Germany) before RNA extraction, in order to isolate pure tumor or normal cell populations. RNA from FFPE samples was isolated using the RecoverAll Total Nucleic Acid Isolation kit (Ambion/Life Technologies, Carlsbad, CA, USA), following our previously reported protocol with modifications to improve RNA yield [PMID:23835716]. RNA was stored at -80ºC until RNA extraction and gene expression validation⁠. In addition, tumor tissues from the same patients were collected for further analysis (not in scope of the presented study). Probes were designed for the 4-gene signature (MMP1, COL4A1, P4HA2 and THBS2) and contained one capture probe linked to biotin and one reporter probe attached to a color-coded molecular tag for each gene sequence, according to the nCounterTM code-set design. RNA samples were randomized using a numerical ID and were then subjected to NanoString nCounterTM analysis by the Princess Margaret Genomics Centre (https://www.pmgenomics.ca), Toronto, ON, Canada. Patient samples were analyzed in two batches consisting of 125 and 152 margins tissue samples. The detailed protocol for mRNA transcript quantification analysis, including sample preparation, hybridization, detection and scanning followed the manufacturer’s recommendations and was described in [PMID: 21549012]. We used 400 ng of total RNA isolated from FFPE tissues for detection of probe signals. Raw data were analyzed using the nCounterTM digital analyzer software (http://www.nanostring.com/support/ncounter/) and gene expression levels were subjected to further bioinformatic and statistical analyses.

Dataset Information

Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation.

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Gene signature predicting recurrence in oral squamous cell carcinoma is characterized by increased oxidative phosphorylation.

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