f3ff5ee51f6b3444f9c78a729a28f46a 255493.pdf 3988ca8455d31c78e8d88472f143f89f141a4efd 255493.pdf 7acf1ee2e7a7de6548ad1b89d4fb06b791266d28394ae6f773941ef08a502480 255493.pdf Title: Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker Subject: Head and neck squamous cell carcinoma (HNSCC) is characterized by high rates of mortality and treatment-related morbidity, underscoring the urgent need for innovative and safe treatment strategies and diagnosis practices. Mitochondrial dysfunction is a hallmark of cancer and can lead to the accumulation of tricarboxylic acid cycle intermediates, such as succinate, which function as oncometabolites. In addition to its role in cancer development through epigenetic events, succinate is an extracellular signal transducer that modulates immune response, angiogenesis and cell invasion by activating its cognate receptor SUCNR1. Here, we explored the potential value of the circulating succinate and related genes in HNSCC diagnosis and prognosis. We determined the succinate levels in the serum of 66 pathologically confirmed, untreated patients with HNSCC and 20 healthy controls. We also surveyed the expression of the genes related to succinate metabolism and signaling in tumoral and nontumoral adjacent tissue and in normal mucosa from 50 patients. Finally, we performed immunohistochemical analysis of SUCNR1 in mucosal samples. The results showed that the circulating levels of succinate were higher in patients with HNSCC than in the healthy controls. Additionally, the expression of SUCNR1, HIF-1, succinate dehydrogenase (SDH) A, and SDHB was higher in the tumor tissue than in the matched normal mucosa. Consistent with this, immunohistochemical analysis revealed an increase in SUCNR1 protein expression in tumoral and nontumoral adjacent tissue. High SUCNR1 and SDHA expression levels were associated with poor locoregional control, and the locoregional recurrence-free survival rate was significantly lower in patients with high SUCNR1 and SDHA expression than in their peers with lower levels (77.1% [95% CI: 48.9–100.0] vs. 16.7% [95% CI: 0.0–44.4], p = 0.018). Thus, the circulating succinate levels are elevated in HNSCC and high SUCNR1/SDHA expression predicts poor locoregional disease-free survival, identifying this oncometabolite as a potentially valuable noninvasive biomarker for HNSCC diagnosis and prognosis. Keywords: oncometabolite; succinate; succinate receptor; metabolism; head and neck cancer;treatment; prognosis Author: Ximena Terra, Victoria Ceperuelo-Mallafré, Carla Merma, Ester Benaiges, Ramon Bosch, Paola Castillo, Joan Carles Flores, Xavier León, Izaskun Valduvieco, Neus Basté, Marina Cámara, Marylène Lejeune, Josep Gumà, Joan Vendrell, Isabel Vilaseca, Sonia Fernández-Veledo and Francesc Xavier Avilés-Jurado Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Apr 1 17:18:30 2021 CEST ModDate: Fri Apr 9 05:38:43 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1784137 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- QLMWAV+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 SXQPWE+VnURWPalladioL Type 1 Custom yes yes no 15 0 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PMKFIB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 149 0 PMKDPH+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 164 0 PMKDPI+PalatinoLinotype CID TrueType Identity-H yes yes yes 167 0 PMKDPJ+PalatinoLinotype TrueType WinAnsi yes yes no 173 0 PMKFIB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 176 0 PMKDPH+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 191 0 PMKDPI+PalatinoLinotype CID TrueType Identity-H yes yes yes 194 0 PMKDPJ+PalatinoLinotype TrueType WinAnsi yes yes no 200 0 PMKFIB+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 203 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2022-03-10 03:03:09 CET RepresentationInformation: 255493.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-03-09 12:25:05 CET Size: 1784137 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 393 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Study Design and Patients Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Measurement of Circulating Succinate Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Gene Expression Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Histology Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Characteristics of the Patients Included in the Study Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Circulating Levels of the Oncometabolite Succinate Are Elevated in Patients with HNSCC Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: SUCNR1 Is Predominantly Expressed in Tumoral Mucosa and Positively Associates with Plasma Succinate Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: SUCNR1 and SDHA Gene Expression in Tumoral Tissue Is Associated with Locoregional Disease-Free Survival Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Relationship between SUCNR1/SDHA Profiles and Clinicopathological Variables Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: SUCNR1/SDHA Profiles Are Independent Predictors of HNSCC Prognosis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Info: Title: Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker Author: Ximena Terra, Victoria Ceperuelo-Mallafré, Carla Merma, Ester Benaiges, Ramon Bosch, Paola Castillo, Joan Carles Flores, Xavier León, Izaskun Valduvieco, Neus Basté, Marina Cámara, Marylène Lejeune, Josep Gumà, Joan Vendrell, Isabel Vilaseca, Sonia Fernández-Veledo and Francesc Xavier Avilés-Jurado Subject: Head and neck squamous cell carcinoma (HNSCC) is characterized by high rates of mortality and treatment-related morbidity, underscoring the urgent need for innovative and safe treatment strategies and diagnosis practices. Mitochondrial dysfunction is a hallmark of cancer and can lead to the accumulation of tricarboxylic acid cycle intermediates, such as succinate, which function as oncometabolites. In addition to its role in cancer development through epigenetic events, succinate is an extracellular signal transducer that modulates immune response, angiogenesis and cell invasion by activating its cognate receptor SUCNR1. Here, we explored the potential value of the circulating succinate and related genes in HNSCC diagnosis and prognosis. We determined the succinate levels in the serum of 66 pathologically confirmed, untreated patients with HNSCC and 20 healthy controls. We also surveyed the expression of the genes related to succinate metabolism and signaling in tumoral and nontumoral adjacent tissue and in normal mucosa from 50 patients. Finally, we performed immunohistochemical analysis of SUCNR1 in mucosal samples. The results showed that the circulating levels of succinate were higher in patients with HNSCC than in the healthy controls. Additionally, the expression of SUCNR1, HIF-1, succinate dehydrogenase (SDH) A, and SDHB was higher in the tumor tissue than in the matched normal mucosa. Consistent with this, immunohistochemical analysis revealed an increase in SUCNR1 protein expression in tumoral and nontumoral adjacent tissue. High SUCNR1 and SDHA expression levels were associated with poor locoregional control, and the locoregional recurrence-free survival rate was significantly lower in patients with high SUCNR1 and SDHA expression than in their peers with lower levels (77.1% [95% CI: 48.9 100.0] vs. 16.7% [95% CI: 0.0 44.4], p = 0.018). Thus, the circulating succinate levels are elevated in HNSCC and high SUCNR1/SDHA expression predicts poor locoregional disease-free survival, identifying this oncometabolite as a potentially valuable noninvasive biomarker for HNSCC diagnosis and prognosis. 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