Dataset Information

Role of Focal Adhesion Kinase in Head and Neck Squamous Cell Carcinoma and Its Therapeutic Prospect.

ABSTRACT: Head and neck cancers are one of the most prevalent cancers globally. Among them, head and neck squamous cell carcinoma (HNSCC) accounts for approximately 90% of head and neck cancers, which occurs in the oral cavity, oral pharynx, hypopharynx and larynx. The 5-year survival rate of HNSCC patients is only 63%, mainly because about 80-90% of patients with advanced HNSCC tend to suffer from local recurrence or even distant metastasis. Despite the more in-depth understanding of the molecular mechanisms underlying the occurrence and progression of HNSCC in recent years, effective targeted therapies are unavailable for HNSCC, which emphasize the urgent demand for studies in this area. Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase that contributes to oncogenesis and tumor progression by its significant function in cell survival, proliferation, adhesion, invasion and migration. In addition, FAK exerts an effect on the tumor microenvironment, epithelial-mesenchymal transition, radiation (chemotherapy) resistance, tumor stem cells and regulation of inflammatory factors. Moreover, the overexpression and activation of FAK are detected in multiple types of tumors, including HNSCC. FAK inhibition can induce cell cycle arrest and apoptosis, significantly decrease cell growth, invasion and migration in HNSCC cell lines. In this article, we mainly review the research progress of FAK in the occurrence, development and metastasis of HNSCC, and put forward the prospects for the therapeutic targets of HNSCC.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7553669 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Role of Focal Adhesion Kinase in Head and Neck Squamous Cell Carcinoma and Its Therapeutic Prospect.

Zhang Yuxi Y Sun Xinchen X

OncoTargets and therapy 20201009

Head and neck cancers are one of the most prevalent cancers globally. Among them, head and neck squamous cell carcinoma (HNSCC) accounts for approximately 90% of head and neck cancers, which occurs in the oral cavity, oral pharynx, hypopharynx and larynx. The 5-year survival rate of HNSCC patients is only 63%, mainly because about 80-90% of patients with advanced HNSCC tend to suffer from local recurrence or even distant metastasis. Despite the more in-depth understanding of the molecular mechan ...[more]

PMID: 33116602

Similar Datasets

Project description:The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Results: Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regulated genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Conclusions: Our findings reveal that BRD4 serves as a novel and critical mediator underlying tumorigenesis and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.

Project description:Recurrent/metastatic head and neck cancer remains a devastating disease with insufficient treatment options. We investigated the MET receptor tyrosine kinase as a novel target for the treatment of head and neck squamous cell carcinoma (HNSCC). MET/phosphorylated MET and HGF expression was analyzed in 121 tissues (HNSCC/normal) by immunohistochemistry, and in 20 HNSCC cell lines by immunoblotting. The effects of MET inhibition using small interfering RNA/two small-molecule inhibitors (SU11274/PF-2341066) on signaling, migration, viability, and angiogenesis were determined. The complete MET gene was sequenced in 66 head and neck cancer tissue samples and eight cell lines. MET gene copy number was determined in 14 cell lines and 23 tumor tissues. Drug combinations of SU11274 with cisplatin or erlotinib were tested in SCC35/HN5 cell lines. Eighty-four percent of the HNSCC samples showed MET overexpression, whereas 18 of 20 HNSCC cell lines (90%) expressed MET. HGF overexpression was present in 45% of HNSCC. MET inhibition with SU11274/PF-2341066 abrogated MET signaling, cell viability, motility/migration in vitro, and tumor angiogenesis in vivo. Mutational analysis of 66 tumor tissues and 8 cell lines identified novel mutations in the semaphorin (T230M/E168D/N375S), juxtamembrane (T1010I/R988C), and tyrosine kinase (T1275I/V1333I) domains (incidence: 13.5%). Increased MET gene copy number was present with >10 copies in 3 of 23 (13%) tumor tissues. A greater-than-additive inhibition of cell growth was observed when combining a MET inhibitor with cisplatin or erlotinib and synergy may be mediated via erbB3/AKT signaling. MET is functionally important in HNSCC with prominent overexpression, increased gene copy number, and mutations. MET inhibition abrogated MET functions, including proliferation, migration/motility, and angiogenesis. MET is a promising, novel target for HNSCC and combination approaches with cisplatin or EGFR inhibitors should be explored.

Dataset Information

Role of Focal Adhesion Kinase in Head and Neck Squamous Cell Carcinoma and Its Therapeutic Prospect.

Publications

Role of Focal Adhesion Kinase in Head and Neck Squamous Cell Carcinoma and Its Therapeutic Prospect.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets