Regulation and function of S100 proteins in pancreatic carcinoma

Pancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide with the survival rate less than 5% because of late diagnosis. Development of PC is complex, it is promoted by the tumour microenvironment and often accompanied by inflammation. Epithelial mesenchymal transition (EMT) is an embryonic genetic program reactivated in cancer. EMT is implicated in the escape from senescence, tumour cell invasiveness, cancer metastasis, and drug resistance. EMT encompasses global reorganisation of the gene expression profiles, loss of epithelial markers and activation of mesenchymal genes. Among the genes affected during EMT are those coding for the members of the S100 protein family. Regulation and function of these genes in PC are, however, insufficiently studied. To link S100 proteins with EMT programs in PC, expression of eleven S100 proteins, a number of epithelial and mesenchymal markers, and several EMT-inducing transcription factors was analysed in a panel of the PC cell lines and clinical samples. I found that two S100 family members, namely S100A4 and S100A6 are induced during EMT in PC. In contrast, S100A14 expression was repressed by EMT-inducing transcription factors. Consistent with this observation, S100A4&A6 and S100A14 respectively activated and repressed invasion of PC cells in zebrafish xenografts. Exosomes isolated from the actively migrated MIA PaCa-2 cells contained high levels of S100A4&A6 proteins, stimulated invasion of the slowly migrating BxPC-3 cells. In a cohort of PC samples, it was observed a trend towards enhanced expression of S100A4 protein in most aggressive tumours. The mechanism of S100A4 activation was investigated in PC. Our data show that in the course of an EMT” mesenchymal” genes, S100A4 and S100A6 are induced via IL-6 and IL-11/STAT3 pathway. Treatment of cells with the STAT3 inhibitor, Stattic, inhibited expression of these genes, and blocked cell invasion in zebrafish xenografts. It has been proposed that uncoupling inflammatory IL/STAT3 signalling from the activation of S100A4 and S100A6 genes may decrease the mortality rate of PC patients.