Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker

Autor segons l'article: Terra, Ximena; Ceperuelo-Mallafre, Victoria; Merma, Carla; Benaiges, Ester; Bosch, Ramon; Castillo, Paola; Flores, Joan Carles; Leon, Xavier; Valduvieco, Izaskun; Baste, Neus; Camara, Marina; Lejeune, Marylene; Guma, Josep; Vendrell, Joan; Vilaseca, Isabel; Fernandez-Veledo, Sonia; Aviles-Jurado, Francesc Xavier

Departament: Medicina i Cirurgia; Ciències Mèdiques Bàsiques; Bioquímica i Biotecnologia

Autor/s de la URV: Avilés Jurado, Francisco Javier / Benaiges Moragrega, Ester / Bosch Príncep, Ramon / Ceperuelo Mallafré, Maria Victoria / Fernandez Veledo, Sonia / Flores Martin, Juan Carlos / Gumà Padró, José / Lejeune, Marylène Marie / Merma Linares, Carla Vanessa / Terra Barbadora, Ximena / Vendrell Ortega, Juan José

Paraules clau: Upregulation; Unclassified drug; Tumor-related gene; Tumor marker; Treatment; Survival rate; Succinic acid; Succinate signaling; Succinate receptor 1; Succinate receptor; Succinate dehydrogenase; Succinate; Signal transduction; Recurrence free survival; Prognosis; Oncometabolite; Non invasive procedure; Middle aged; Metabolism; Male; Major clinical study; Immunohistochemistry; Hypoxia inducible factor 1alpha; Human tissue; Human; Head and neck squamous cell carcinoma; Head and neck cancer; Genetic association; Gene expression regulation; Gene expression; G protein coupled receptor; Female; Disease free survival; Disease association; Controlled study; Cancer prognosis; Cancer diagnosis; Blood analysis; Article; Aged; Adult

Resum: Simple Summary Emerging evidence points to succinate as an important oncometabolite in cancer development; however, the contribution of the succinate-SUCNR1 axis to cancer progression remains unclear. Head and neck squamous cell carcinoma (HNSCC) is associated with disease and treatment-related morbidity so there is an urgent need for innovation in treatment and diagnosis practices. Our aim was to evaluate the potential of the succinate-related pathway as a diagnostic and prognostic biomarker in HNSCC. The circulating succinate levels are increased in HNSCC, being a potential noninvasive biomarker for HNSCC diagnosis. Moreover, the succinate receptor (SUCNR1) and genes related to succinate metabolism, which are predominantly expressed in the tumoral mucosa as compared with healthy tissue, are positively associated with plasma succinate. Remarkably, we found that SUCNR1 and SDHA expression levels predict prognosis. 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 alpha, 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.

Àrees temàtiques: Oncology; Medicina iii; Cancer research

Accès a la llicència d'ús: https://creativecommons.org/licenses/by/3.0/es/

Adreça de correu electrònic de l'autor: juancarlos.flores@urv.cat; carlavanessa.merma@urv.cat; ramon.bosch@urv.cat; victoria.ceperuelo@urv.cat; marylenemarie.lejeune@urv.cat; franciscojavier.aviles@urv.cat; carlavanessa.merma@urv.cat; ramon.bosch@urv.cat; ester.benaiges@estudiants.urv.cat; ester.benaiges@estudiants.urv.cat; sonia.fernandez@urv.cat; ximena.terra@urv.cat; jose.guma@urv.cat; jvortega@iispv.cat

Data d'alta del registre: 2025-01-08

Versió de l'article dipositat: info:eu-repo/semantics/publishedVersion

Enllaç font original: https://www.mdpi.com/2072-6694/13/7/1653

URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/

Referència a l'article segons font original: Cancers. 13 (7): 1653-

Referència de l'ítem segons les normes APA: Terra, Ximena; Ceperuelo-Mallafre, Victoria; Merma, Carla; Benaiges, Ester; Bosch, Ramon; Castillo, Paola; Flores, Joan Carles; Leon, Xavier; Valduvie (2021). Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker. Cancers, 13(7), 1653-. DOI: 10.3390/cancers13071653

DOI de l'article: 10.3390/cancers13071653

Entitat: Universitat Rovira i Virgili

Any de publicació de la revista: 2021

Tipus de publicació: Journal Publications