Investigating JUNB and CXCR4 expression in Circulating Tumor Cells and exosomes derived from Small Cell Lung Cancer (SCLC) patients
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ABSTRACT:
PROVIDER: PRJNA998342 | ENA |
REPOSITORIES: ENA
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Project description:The enhanced metastatic ability of small-cell lung cancer warrants the discovery of prognostic biomarkers to support decisions during the course of the disease. We have previously demonstrated the clinical significance of JUNB and CXCR4 expression in circulating tumor cells (CTCs) from breast and non-small cell lung cancer (NSCLC). patients. In the present study, we aimed to explore the expression levels of the aforementioned biomarkers in patients’ CTCs and plasma-derived exosomes. One hundred SCLC patients at baseline were enrolled in the study; exosome isolation was performed in 58 of them. Cytospins were analyzed using the VyCAP system and exosomes were characterized based on their molecular and transcriptomic profile. JUNB and CXCR4 were expressed in the majority of the CTCs. Protein exosomal expression of both biomarkers in patients was significantly different compared to healthy donors (p = 0.003 and p = 0.027, respectively), while a high discriminative ability was observed in patients overexpressing JUNB and CXCR4 in their exosomes (c-statistic = 0.949 and c-statistic = 0.903 respectively). The presence of JUNB and/or CXCR4 in CTCs was associated with poorer OS (p = 0.025). CXCR4 exosomal overexpression correlated with the presence of CTCs and their phenotypes. Lastly, miRNA profiling on 4 SCLC patients, indicated a multitude of biological processes and signaling pathways implicated in SCLC pathogenesis. Our study is the first attempt to evaluate two different aspects of liquid biopsy (CTCs and exosomes) in SCLC patients, regarding JUNB and CXCR4 expression, aiming to provide a potential new prognostic and/ or diagnostic approach.
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Project description:This study is designed to determine the direct target genes of JunB transcription factor in human keratinocytes Mice with epidermal deletion of JunB transcription factor displayed a psoriasis-like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here, we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss-of-function which included an upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were TNFa, CCL2, CXCL10, IL6R and SQSTM1, an adaptor protein involved in NF-kB activation. ChIP-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 through binding to a consensus AP-1 cis-element located around 2 Kb upstream of SQSTM1-trasncription start site. Similar to JunB loss-of-function, SQSTM1-overexpression induced TNFa, CCL2 and CXCL10. Conversely, NF-kB-inhibition genetically with a mutant IkBa or pharmacologically with PDTC prevented cytokine, but not IL6R, induction by JunB-deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB-suppression of NF-kB-dependent inflammation.
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