NOTCH1 Intracellular Domain and the Tumor Microenvironment as Prognostic Markers in HNSCC

Abstract

(1) Background: NOTCH1 is the second most common mutated gene in whole-exome sequencing of HNSCC. The aim of this project was to gain further insight into the relevance of NOTCH1 in HNSCC, potentially establishing NOTCH1 as a prognostic marker or therapeutic target; (2) Methods: NOTCH1 was silenced via RNA interference in six HNSCC cell lines and the impact was evaluated in migration and proliferation assays. Subsequently, the protein expression of NOTCH1 intracellular domain (NICD) and NOTCH1 mRNA expression were examined in 70 oropharyngeal squamous cell cancer tissue samples. Lastly, the NICD expression was compared with the local infiltration of lymphocytes, measured with the immunoscore; (3) Results: Knockdown of NOTCH1 decreased migration and proliferation. A high NICD expression was associated with lower OS. A high immunoscore resulted in significantly better OS. NICD expression was independent of the immunoscore and as a whole differentiated three distinct prognostic groups; (4) Conclusions: These data suggest that NOTCH1 is involved in migration and proliferation of HNSCC cell lines. In vivo, NICD expression was associated with overall survival and could, therefore, be used as a prognostic marker. NICD expression differs from NOTCH1 mRNA levels, potentially explaining the previously suggested bimodal role as an oncogene and tumor suppressor in HNSCC.

A composite score based on immune-related gene prognostic index and m6A risk score of head and neck squamous cell carcinoma

“…TP53 mutation is not only the most common genetic event in cancer, but is also associated with more aggressive disease and poorer patient outcomes in many cancers, especially in HNSCC (Poeta et al, 2007;Leroy et al, 2014). The Notch signaling pathway is known to be an evolutionarily Frontiers in Genetics frontiersin.org conserved intercellular signaling pathway, and NOTCH1 mutation is associated with HNSCC (Schmidl et al, 2022;Zhou et al, 2022). The mutation rate of NOTCH1 gene in subgroup B (23%) is higher than that in other groups, which may be the reason why HNSCC patients in subgroup B have worse OS than those in subgroup C. It also means that some HNSCC patients may benefit from anti-NOTCH1 therapy.…”

A composite score based on immune-related gene prognostic index and m6A risk score of head and neck squamous cell carcinoma

“…TP53 mutation is not only the most common genetic event in cancer, but is also associated with more aggressive disease and poorer patient outcomes in many cancers, especially in HNSCC [20,21]. The Notch signaling pathway is known to be an evolutionarily conserved intercellular signaling pathway, and NOTCH1 mutation is associated with HNSCC [22,23]. The mutation rate of NOTCH1 gene in subgroup B (23%) is higher than that in other groups, which may be the reason why HNSCC patients in subgroup B have worse OS than those in subgroup C. It also means that some HNSCC patients may bene t from anti-NOTCH1 therapy.…”

Modulation of Notch Signaling by Small-Molecular Compounds and Its Potential in Anticancer Studies

“…GoF mutations, such as those typical in T-ALL, are not found in HNSCC, and functional alterations are mainly related to high expression levels. Recent publications have reported a diagnostic and prognostic association of high-level NOTCH receptor expression in HNSCC [ 78 ] in European patients. Other reports of GoF alteration in Notch signaling components, including the ligands, have been predominantly observed in Asian patient cohorts, in which many suffer from different risk factors compared to European and American patients [ 79 ].…”