Some of the upregulated genes comprised genes with important functions in the immune response and proliferation, such as claudin 4 (CLDN4), orosomucoid 1 (ORM1), insulin-like growth factor binding protein 2 (IGFBP2), cytochrome P450, family 26, subfamily A, polypeptide 1 (CYP26A1), and growth arrest-specific 1 (GAS1).
Out of these 12 genes, ORM1, HMGCS2, NOCT, NNMT, CLDN4, and PON3 were confirmed to be differentially expressed in both DON- and ZEN-treated liver samples.
CLDN4 is known to promote pancreatic cancer and gastric carcinoma and has also been shown to cause impaired function of tight junctions, which are in turn related to tumor differentiation .
The CAMs pathway regulates the expression of the immune response-related genes, namely, CLDN4, SLA-1, SLA-3, SLA-5, and SLA-7, which were downregulated mycotoxin-treated livers.
Those genes included VEGF, BCL2, claudin 4 (CLDN4
), Yes-associated protein 1 (YAP1), and c-MET, and each was found to significantly predict recurrence-free survival following radiotherapy or chemoradiotherapy.
Moreover, Oct4 is able to bind to the upstream regulatory region of Cdx2 and Cldn4
, genes that are specific for trophectoderm, to repress their expression .
APOBEC3C is connected to CLDN4
with proteinprotein interaction mediated by SHBG (Warde-Farley et al., 2010), which is a trans-membrane protein that might negatively influence fertility rates and is associated with assisted reproduction outcome (Serafini et al., 2009).
(131,132) Other frequently hypomethylated genes, including CLDN4
(chromosome arm 7q, encoding claudin-4), LCN2 (chromosome arm 9q, encoding lipocalin-2), SFN/14-3-3[sigma] (chromosome arm 18q), TFF2 (chromosome arm 21q, encoding trefoil factor 2), MSLN (chromosome arm 16p, encoding mesothelin), and PSCA (chromosome arm 8q, encoding prostate stem cell antigen), are overexpressed in pancreatic cancer cells in comparison with normal pancreatic duct.132 With oligonucleotide microarray technologies, 2 additional genes, S100P (chromosome arm 4p) and SERPINB5 (chromosome arm 18q, encoding maspin), have been identified as being hypomethylated and are overexpressed.6 A selected list of genes that are aberrantly hypomethylated in pancreatic cancer is summarized in Table 3.
These genes encode components of desmosomes (DSG2), gap junctions (CX26), tight junctions (CLDN4
, CLDN7), the cornified envelope (SPRRIA, 2A, 2B, 2E, 2F, 2G, 2I, 2J), intermediate filaments (KRT19), and a variety of cell-surface and extracellular-matrix glycoproteins (SPP1, BGP1, BGP2, MUC1, TROP2, CLU).