Genomic and Transcriptomic Alterations Associated with STAT3 Activation in Head and Neck Cancer

Abstract

BackgroundHyperactivation of STAT3 via constitutive phosphorylation of tyrosine 705 (Y705) is common in most human cancers, including head and neck squamous carcinoma (HNSCC). STAT3 is rarely mutated in cancer and the (epi)genetic alterations that lead to STAT3 activation are incompletely understood. Here we used an unbiased approach to identify genomic and epigenomic changes associated with pSTAT3(Y705) expression using data generated by The Cancer Genome Atlas (TCGA).Methods and FindingsMutation, mRNA expression, promoter methylation, and copy number alteration data were extracted from TCGA and examined in the context of pSTAT3(Y705) protein expression. mRNA expression levels of 1279 genes were found to be associated with pSTAT3(705) expression. Association of pSTAT3(Y705) expression with caspase-8 mRNA expression was validated by immunoblot analysis in HNSCC cells. Mutation, promoter hypermethylation, and copy number alteration of any gene were not significantly associated with increased pSTAT3(Y705) protein expression.ConclusionsThese cumulative results suggest that unbiased approaches may be useful in identifying the molecular underpinnings of oncogenic signaling, including STAT3 activation, in HNSCC. Larger datasets will likely be necessary to elucidate signaling consequences of infrequent alterations.

Quantification of STAT3 and VEGF expression for molecular diagnosis of lymph node metastasis in breast cancer

“…[ 8 ] STAT3 has been closely linked to various types of cancer, such as pancreatic cancer, stomach cancer, head and neck cancer, and thyroid carcinoma, and contributes to cancer progression by upregulating oncogenes. [ 12 – 15 ] Some studies have suggested that constitutively active STAT3 binds to one of binding sites of VEGF, which upregulates VEGF expression, promotes angiogenesis, and increases the risk of tumorigenesis. [ 19 ] Varney and Singh [ 7 ] observed that the VEGF-C-VEGFR-3/Flt4 (VEGFR-3) autocrine signaling pathway regulates the survival and proliferation of breast tumor cells.…”

“…[ 8 – 11 ] Moreover, constitutive expression of signal transducer and activator of transcription 3 (STAT3) is significantly associated with tumor formation, migration, and invasion in various cancers, such as papillary thyroid carcinoma, pancreatic cancer, head and neck cancer, and gastric cancer. [ 12 – 15 ] However, the mechanisms underlying positive correlation between expression of STAT3 in breast cancer patients and lymph node metastasis remain unclear.…”

Clinicopathologic implications of the miR-197/PD-L1 axis in oral squamous cell carcinoma

“…In addition to miR-197, PD-L1 is regulated by other microRNAs, including miR-138-5p, miR-513, miR-570, miR-34a, and miR-200, the functions of which have not yet been elucidated in OSCC [ 14 - 18 ]. Considering previously reported clinically relevant signaling pathways involving CKS1B and STAT3 in OSCC and the known miR-197/CKS1B/STAT3/PD-L1 pathway [ 12 , 13 , 19 - 21 ], we focused on the miR-197/PD-L1 axis and TILs.…”

Modulators of Redox Metabolism in Head and Neck Cancer

“…Using CasP subtyping, HNSCC patients were stratified into two distinct groups, including (i) patients with mutations in TLR signaling who have better OS and (ii) patients with mutations in T and B cell receptor signaling who have poorer survival (179). Also, another study identified genomic and/or epigenomic changes that lead to STAT3 activation in HNSCCs using data generated by the TCGA and the TCPA programs (233). The authors identified that STAT3 expression is associated with disease stage, nodal status, tumor size, PFS, and OS in early stage oral HNSCCs.…”