Search for novel STAT3-dependent genes reveals SERPINA3 as a new STAT3 target that regulates invasion of human melanoma cells.
Dorota W KuleszaKavita RamjiMarta MaleszewskaJakub MieczkowskiMichal DabrowskiSalem ChouaibBozena KaminskaPublished in: Laboratory investigation; a journal of technical methods and pathology (2019)
Transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers and promotes uncontrolled tumor growth and progression through multiple mechanisms. Compelling evidence shows tissue and cell-specific sets of STAT3 targets. Transcriptional targets of STAT3 in melanoma cells are largely unknown. Malignant melanoma is a deadly disease with highly aggressive and drug-resistant behavior. Less than 10% of patients with advanced melanomas reach the 5-year survival, partly due to the aggressive character of the tumor and ineffectiveness of current therapeutics for treating metastatic melanoma. STAT3 is constitutively activated in melanoma cells and plays important roles in its growth and angiogenesis in tumor xenograft studies. Moreover, highly metastatic melanoma cells have higher levels of active STAT3 than poorly metastatic ones. To identify genes that are driven by STAT3 in human melanoma cells, we performed JAK/STAT signaling specific and global gene expression profiling of human melanoma cells with silenced STAT3 expression. For selected genes, we performed computational identification of putative STAT3-binding sites and validated direct interactions STAT3 with defined promoters by using chromatin immunoprecipitation followed by qPCR. We found that STAT3 knockdown does not affect human melanoma cell viability, proliferation, or response to chemotherapeutics. We show that STAT3 regulates a discrete set of genes in melanoma cells, including SERPINA3, a novel STAT3 target gene, which is functionally involved in regulation of melanoma migration and invasion. Knockdown of STAT3 impaired cell migration and invasion, in part via regulation of its transcriptional target SERPINA3. Our results present novel targets and functions of STAT3 in melanoma cells.
Keyphrases
- cell proliferation
- transcription factor
- endothelial cells
- genome wide
- drug resistant
- squamous cell carcinoma
- small cell lung cancer
- stem cells
- poor prognosis
- genome wide identification
- dna damage
- immune response
- multidrug resistant
- signaling pathway
- small molecule
- long non coding rna
- induced pluripotent stem cells
- acinetobacter baumannii
- bioinformatics analysis
- pluripotent stem cells
- toll like receptor
- cell therapy
- binding protein
- cell migration
- dna binding
- heat shock protein