Mechanism of HPSE Gene SNPs Function: From Normal Processes to Inflammation, Cancerogenesis and Tumor Progression.

Single Nucleotide Polymorphisms (SNPs) is the substitution of a single nucleotide, stably inherited, highly abundant, and distributed throughout the genome. Up today 9746 SNPs were found in the HPSE gene. During 12 years 21 SNPs were analyzed in normal and pathological samples. The most prominent SNPs are rs4693608, rs11099592, rs4693084, and rs4364254. These SNPs were found in correlation with heparanase mRNA and protein expression among healthy persons. Moreover, an association of the HPSE gene SNPs with inflammatory processes, cancer development and progression was detected. SNP investigation allowed the identification of strong HPSE gene enhancer in the intron 2. In normal leukocytes, heparanase binds to the enhancer region and regulates HPSE gene expression via negative feedback in rs4693608 SNP-dependent manner. In malignant cells, heparanase halted self-regulation of the enhancer region. Instead of heparanase, the helicase-like transcription factor (HLTF) binds to the regulatory region. These and subsequent studies will elucidate how modification in the HPSE enhancer region could be applied to develop new approaches for cancer treatment.