Abstract
BackgroundNotch pathway plays a complex role depending on cellular contexts: promotes stem cell maintenance or induces terminal differentiation in potential cancer-initiating cells; acts as an oncogene in lymphocytes and mammary tissue or plays a growth-suppressive role in leukemia, liver, skin, and head and neck cancer. Here, we present a novel clinical and functional significance of NOTCH1 alterations in early stage tongue squamous cell carcinoma (TSCC).Patients and MethodsWe analyzed the Notch signaling pathway in 68 early stage TSCC primary tumor samples by whole exome and transcriptome sequencing, real-time PCR based copy number, expression, immuno-histochemical, followed by cell based biochemical and functional assays.ResultsWe show, unlike TCGA HNSCC data set, NOTCH1 harbors significantly lower frequency of inactivating mutations (4%); is somatically amplified; and, overexpressed in 31% and 37% of early stage TSCC patients, respectively. HNSCC cell lines over expressing NOTCH1, when plated in the absence of attachment, are enriched in stem cell markers and form spheroids. Furthermore, we show that inhibition of NOTCH activation by gamma secretase inhibitor or shRNA mediated knockdown of NOTCH1 inhibits spheroid forming capacity, transformation, survival and migration of the HNSCC cells suggesting an oncogenic role of NOTCH1 in TSCC. Clinically, Notch pathway activation is higher in tumors of non-smokers compared to smokers (50% Vs 18%, respectively, P=0.026) and is also associated with greater nodal positivity compared to its non-activation (93% Vs 64%, respectively, P=0.029).ConclusionWe anticipate that these results could form the basis for therapeutic targeting of NOTCH1 in tongue cancer.
Highlights
Recent large-scale genome wide studies have underscored a complex role of NOTCH1 as a candidate tumor suppressor harboring inactivating mutation and deletions, as well as a driver of tumorigenesis harboring activating missense mutations and amplifications in a context dependent manner in HNSCC, and other cancers [1,2,3,4,5,6,7,8,9,10]
We show that inhibition of NOTCH activation by gamma secretase inhibitor or shRNA mediated knockdown of NOTCH1 inhibits spheroid forming capacity, transformation, survival and migration of the HNSCC cells suggesting an oncogenic role of NOTCH1 in tongue squamous cell carcinoma (TSCC)
Notch pathway activation is higher in tumors of non-smokers compared to smokers (50% Vs 18%, respectively, P=0.026) and is associated with greater nodal positivity compared to its non-activation (93% Vs 64%, respectively, P=0.029)
Summary
Recent large-scale genome wide studies have underscored a complex role of NOTCH1 as a candidate tumor suppressor harboring inactivating mutation and deletions , as well as a driver of tumorigenesis harboring activating missense mutations and amplifications in a context dependent manner in HNSCC, and other cancers [1,2,3,4,5,6,7,8,9,10]. Notch signaling pathway plays a significant role in the maintenance of cancer stem-like population of cells (CSCs) in several human cancers [11,12,13,14,15]. To understand the role of Notch signaling pathway in early-stage (T1-T2) tongue tumors, we examined the mutational landscape, copy number alterations and differential expression of receptor, ligands, modifiers and target genes of the Notch pathway, along with effect of genetic and pharmacologic perturbation of Notch pathway on cancer stem-like cells (CSCs) features of HNSCC cells. Notch pathway plays a complex role depending on cellular contexts: promotes stem cell maintenance or induces terminal differentiation in potential cancer-initiating cells; acts as an oncogene in lymphocytes and mammary tissue or plays a growth-suppressive role in leukemia, liver, skin, and head and neck cancer. We present a novel clinical and functional significance of NOTCH1 alterations in early stage tongue squamous cell carcinoma (TSCC)
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