The NOTCH Pathway in Head and Neck Squamous Cell Carcinoma

Comprehensive genomic analyses have been performed for head and neck squamous cell carcinoma (HNSCC), revealing a significant rate of NOTCH1 mutations and identifying NOTCH1 as the second most frequently mutated gene after TP53. Most NOTCH1 mutations are considered inactivating, indicating that NOTCH1 is a tumor suppressor gene. On the other hand, cohorts from Asian populations with HNSCC have shown activating NOTCH1 mutations. HNSCC with NOTCH1 mutations have a worse prognosis than the NOTCH1 wild-type tumors. Additional data on other NOTCH family members have shown that NOTCH promotes HNSCC progression. NOTCH family members, including NOTCH pathway genes, are upregulated in HNSCC compared with normal tissues, and inhibition of the NOTCH pathway decreases cell proliferation and invasion. NOTCH activity in HNSCC is therefore contextual, and NOTCH in HNSCC is considered to have a bimodal role as a tumor suppressor and an oncogene. In this review, recent understandings of NOTCH pathway genes, including NOTCH genes, in HNSCC are described. In addition, the implications of NOTCH pathway alteration for HNSCC-specific NOTCH-targeted cancer therapy are explored.

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Loss of Heterozygosity at the 9p21–24 Region and Identification of BRM as a Candidate Tumor Suppressor Gene in Head and Neck Squamous Cell Carcinoma

Cancer Investigation ◽

10.1080/07357900802563010 ◽

2009 ◽

Vol 27 (6) ◽

pp. 661-668 ◽

Cited By ~ 16

Author(s):

Esra Gunduz ◽

Mehmet Gunduz ◽

Mahmoud Al Sheik Ali ◽

Levent Beder ◽

Ryo Tamamura ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Suppressor ◽

Cell Carcinoma ◽

Head And Neck ◽

Tumor Suppressor Gene ◽

Loss Of Heterozygosity ◽

Squamous Cell ◽

Suppressor Gene ◽

Neck Squamous Cell Carcinoma ◽

Candidate Tumor Suppressor Gene

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Abstract 5884:4EBP1is a tumor suppressor gene unleashed by mTOR inhibition in head and neck squamous cell carcinoma

10.1158/1538-7445.am2018-5884 ◽

2018 ◽

Author(s):

Zhiyong Wang ◽

Daniel Martin ◽

Lynn Vitale-Cross ◽

Xiaodong Feng ◽

Alfredo A. Molinolo ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Suppressor ◽

Cell Carcinoma ◽

Head And Neck ◽

Tumor Suppressor Gene ◽

Squamous Cell ◽

Suppressor Gene ◽

Neck Squamous Cell Carcinoma ◽

Mtor Inhibition

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ING Genes Work as Tumor Suppressor Genes in the Carcinogenesis of Head and Neck Squamous Cell Carcinoma

Journal of Oncology ◽

10.1155/2011/963614 ◽

2011 ◽

Vol 2011 ◽

pp. 1-11 ◽

Cited By ~ 14

Author(s):

Xiaohan Li ◽

Keiji Kikuchi ◽

Yasuo Takano

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Suppressor ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Tumor Suppressor Genes ◽

Current Knowledge ◽

Suppressor Gene ◽

Neck Squamous Cell Carcinoma ◽

Critical Event

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world. The evolution and progression of HNSCC are considered to result from multiple stepwise alterations of cellular and molecular pathways in squamous epithelium. Recently, inhibitor of growth gene (ING) family consisting of five genes,ING1toING5, was identified as a new tumor suppressor gene family that was implicated in the downregulation of cell cycle and chromatin remodeling. In contrast, it has been shown thatING1andING2play an oncogenic role in some cancers, this situation being similar to TGF-β. In HNSCC, theINGfamily has been reported to be downregulated, and ING translocation from the nucleus to the cytoplasm may be a critical event for carcinogenesis. In this paper, we describe our recent results and briefly summarize current knowledge regarding the biologic functions ofINGin HNSCC.

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NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

Cells ◽

10.3390/cells9122677 ◽

2020 ◽

Vol 9 (12) ◽

pp. 2677

Author(s):

Pooja A. Shah ◽

Chenfei Huang ◽

Qiuli Li ◽

Sawad A. Kazi ◽

Lauren A. Byers ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Tumor Suppressor ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Neck Squamous Cell Carcinoma ◽

Tumor Suppressor Function ◽

Notch1 Signaling ◽

Suppressor Function ◽

Notch1 Mutations

Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1’s role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer’s genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.

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