Abstract
Cervical cancer (CC) is associated with alterations in immune system balance, which is primarily due to a shift from Th1 to Th2 and the unbalance of Th17/Treg cells. Using in silico DNA copy number analysis, we have demonstrated that ~20% of CC samples exhibit gain of 8q22.3 and 19q13.31; the regions of the genome that encodes the KLF10 and PSG genes, respectively. Gene expression studies demonstrated that there were no alterations in KLF10 mRNA expression, whilst the PSG2 and −5 genes were up-regulated by 1.76 and 3.97-fold respectively in CC compared to normal tissue controls. siRNA and ChIP experiments in SiHa cells have demonstrated that KLF10 participates in immune response through regulation of IL6, IL25 and PSG2 and PSG5 genes. Using cervical tissues from KLF10−/− mice, we have identified down-regulation of PSG17, −21 and −23 and IL11. These results suggest that KLF10 may regulate immune system response genes in cervical cancer among other functions. KLF10 and PSG copy number variations and alterations in mRNA expression levels could represent novel molecular markers in CC.
Highlights
Cervical cancer (CC) is associated with alterations in immune system balance, which is primarily due to a shift from Th1 to Th2 and the unbalance of Th17/Treg cells
Krüppel like factors (KLF’s) are a family of transcription factors that participate in various aspects of cellular growth, proliferation and differentiation[9]
In this report we have analyzed the molecular alterations of KLF10 in CC and have identified potential KLF10 target genes by means of DNA copy number variation (CNV) and mRNA transcription using microarrays, in silico analyses and putative transcriptional regulatory networks using gene knock-down approaches in vitro and in vivo
Summary
Cervical cancer (CC) is associated with alterations in immune system balance, which is primarily due to a shift from Th1 to Th2 and the unbalance of Th17/Treg cells. This is mediated in part through the supply of bioactive molecules to the tumor microenvironment These include growth factors, survival factors, pro-angiogenic factors, extracellular matrix-modifying enzymes, as well as the inductive signals that lead to activation of epithelial-mesenchymal transition (EMT)[2]. As well as chemokines such as CCL28 are known to exert these pro-inflammatory effects Expression of these molecules in the tumor microenvironment is tightly regulated by transcription factors. Krüppel like factors (KLF’s) are a family of transcription factors that participate in various aspects of cellular growth, proliferation and differentiation[9] This family is characterized by three C2H2-type zinc finger domains that bind to either CACCC elements or GC boxes in the promoter of target genes to regulate transcriptional activity and gene expression[9]. In this report we have analyzed the molecular alterations of KLF10 in CC and have identified potential KLF10 target genes by means of DNA copy number variation (CNV) and mRNA transcription using microarrays, in silico analyses and putative transcriptional regulatory networks using gene knock-down approaches in vitro and in vivo
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