Comparative genomic analysis suggests FOXP3 facilitates tumor evasion against immunosurveillance by transcriptionally upregulating proteinase inhibitor 9

The serpinB9 protein, known as proteinase inhibitor 9 (PI-9) in human, can potently inhibit the proteinase, granzyme B, which is the major granzyme immune system cells use to kill intracellular pathogen infected or neoplastic cells. Over-expression of PI-9 in tumor cells is considered as a mechanism for tumor evasion against immunosurveillance carried out by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. We analyzed the upstream, downstream and intronic regions of serpinB9 from nine vertebrate genomes. Three well-conserved non-simple-repeat regions were identified, which locate at ~8 kb upstream (in human), between exons 3 and 4, between exons 4 and 5, respectively. Using the Transfac database, we found a few transcription factor binding motifs matching the conserved regions, including motifs for FOXP3, GATA-4, HNF-1, HNF-3beta, Pax, Evi-1 and Nkx2-5. We used a Poisson distribution to assess the significance of the number of occurrences of these motifs in the conserved regions. FOXP3 turned out to be significant, with p-value = 0.0015. Overexpression of FOXP3 was previously shown to be associated with poor prognosis of ovarian cancer. Our finding suggests a mechanistic link between the overexpression of FOXP3 and cancer -FOXP3 transcriptionally up-regulates PI-9, which facilitates tumor evasion by by-passing immunosurveillance.