Abstract
Simple SummaryIn the head and neck, a large proportion of squamous cell carcinoma demonstrate a mutation of the NOTCH1 gene. The aim of this project was to investigate the role of NOTCH1 and immunological characteristics and highlight a potential rationale for therapy. We found that a high expression of NOTCH1 intracellular domain in these patients is associated with reduced overall survival. In vitro experiments additionally showed a reduction of migration and proliferation of cancer cells when NOTCH1 was knocked down. NOTCH1 is, therefore, most likely involved in migration and proliferation of head and neck squamous cell carcinoma and is a prognostic marker in these patients.(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.
Highlights
With more than 650,000 cases each year, head and neck cancer (HNC) are one of the most common cancer entities worldwide [1]
NOTCH1 Is Involved in Migration and Proliferation of HNSCC Cell Lines
The effect of siRNA-mediated NOTCH1 knockdown, inhibition of NOTCH1 signaling via DAPT and stimulation with DLL4 on migration and proliferation was examined in three human papillomavirus (HPV)– and three HPV+ HNSCC cell lines (UD-SCC-5 (UD5), UD-SCC-7 (UD7), UPCISCC-111 (UP111), UD-SCC-2 (UD2), UPCI-SCC-154 (UP154), and 93-VU-147T (93VU))
Summary
With more than 650,000 cases each year, head and neck cancer (HNC) are one of the most common cancer entities worldwide [1]. While the most frequent risk factors remain alcohol and tobacco use [2,3], the incidence of a subgroup of oropharyngeal cancer caused by high-risk human papillomavirus (HPV) infection is increasing steadily. -positive HNSCC differ greatly in prognosis, mutational burden, and molecular pathogenesis. Conventional therapy involves surgery and radio/chemotherapy, with a substantial rate of recurrence [4]. Patients with a recurring tumor have a poor median OS [5]. The need to improve treatment in these patients is hindered by the heterogeneous nature of HNSCC. Finding a molecular target for systemic therapy or as a new prognostic marker remains a challenging task [6,7]. Even though NOTCH1 has been identified as one of the most commonly mutated genes in HNSCC, the discussion about its role is still controversial
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