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Published on: October 9, 2016
Genomic and Transcriptomic Alterations Associated with STAT3 Activation in Head and Neck Cancer
Noah D Peyser1, Kelsey Pendleton2, William E Gooding3
1Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, CA, United States of America, 94143.
Background:
Hyperactivation 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 Findings:
Mutation, 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.
Conclusions:
These 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.
Insights
STAT3 activation is common in head and neck cancers but its causes are unclear. Unbiased analysis of TCGA data revealed gene expression changes, not mutations, linked to STAT3 phosphorylation in HNSCC.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Constitutive phosphorylation of Signal Transducer and Activator of Transcription 3 (STAT3) at tyrosine 705 (pSTAT3(Y705)) is prevalent in human cancers, including head and neck squamous cell carcinoma (HNSCC).
- The underlying genetic and epigenetic alterations driving STAT3 activation in cancer are not fully understood, as STAT3 itself is rarely mutated.
- The Cancer Genome Atlas (TCGA) provides a comprehensive resource for investigating cancer-related genomic and epigenomic changes.
Purpose of the Study:
- To identify genomic and epigenomic alterations associated with STAT3 activation in HNSCC using an unbiased approach.
- To correlate pSTAT3(Y705) protein expression with various molecular data from TCGA, including mutations, mRNA expression, promoter methylation, and copy number alterations.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) dataset, extracting mutation, mRNA expression, promoter methylation, and copy number alteration data.
- Examined the association between these molecular features and pSTAT3(Y705) protein expression levels.
- Validated the association between pSTAT3(Y705) and caspase-8 mRNA expression using immunoblot analysis in HNSCC cell lines.
Main Results:
- A significant association was found between pSTAT3(Y705) expression and the mRNA levels of 1279 genes.
- The expression of caspase-8 mRNA was confirmed to be associated with pSTAT3(Y705) expression.
- No significant association was observed between increased pSTAT3(Y705) protein expression and gene mutations, promoter hypermethylation, or copy number alterations.
Conclusions:
- Unbiased analytical approaches are valuable for uncovering the molecular mechanisms driving oncogenic signaling pathways like STAT3 activation in HNSCC.
- The study highlights that gene expression changes, rather than direct genetic or epigenetic alterations, may be more closely linked to STAT3 activation in HNSCC.
- Larger datasets are required to fully elucidate the downstream signaling effects of less frequent genetic alterations potentially influencing STAT3 activation.
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