Colorectal cancer (CRC) represents one of the highest incidences of
cancers worldwide.
Phosphatidylinositol glycan, class K (PIGK), is a crucial member of the
glycosyl-phosphatidylinositol transamidase (GPIT)
protein complex that attaches a diverse group of macromolecules to the plasma membrane of eukaryotes. However, the precise role of PIGK in
tumorigenesis remains largely unknown. Recently, we reported low expression of PIGK
protein in primary
tumors compared to paired normal tissues of
colorectal cancer (CRC) patients. To understand the mechanism underlying this phenomenon, we performed sequencing of all 10 exons of the PIGK gene in 45 CRC patients. Corresponding PIGK
protein expression was also evaluated in these patients by immunohistochemistry. No mutation was detected in the coding regions, however, we found a single nucleotide polymorphism (C/C→C/G or G/G; rs1048575) in the
3'UTR of the PIGK gene in 67% (30/45) of the patients. Most of the patients (22/26, 85%) with the altered alleles were of Jewish origin. In comparison, 47% (8/17) of the Arabian patients exhibited the altered C/G alleles. We observed a significantly low (p<0.002) expression of PIGK
protein in the patients with the altered alleles (C/G or G/G) compared to the ancestral alleles (C/C). Similarly to the CRC patients, we also examined 5 HCC patients and two HCC cell lines (Hep3B and HepG2) for PIGK genotype (SNP-1048575) and corresponding
protein expression. We observed altered alleles (C/G or G/G) and corresponding low PIGK
protein expression in 4 out of 5 (80%) primary HCC
tumors. Among the HCC cell lines, HepG2 line exhibited ancestral C/C alleles, whereas Hep3B showed altered C/G alleles. Similar to the HCC patients, Hep3B line with the altered alleles (C/G) exhibited significantly low (Student's t-test, p<0.002) PIGK
protein expression compared to the Hep3B line carrying the ancestral (C/C) alleles. To examine the exogenous PIGK
protein expression status, we transiently transfected both HepG2 (C/C alleles) and Hep3B (C/G alleles) cell lines with wt-PIGK constructs. We detected exogenously expressed PIGK
protein in HepG2 (C/C) cells, but no PIGK expression was detectable in Hep3B (C/G) cells at either
mRNA or
protein level. Our results demonstrate, for the first time, a link between the SNP 1048575 and low PIGK expression in CRC/HCC patients and also suggest a possible association between altered PIGK expression and
disease susceptibility.