A single nucleotide polymorphism in the human PIGK gene associates with low PIGK expression in colorectal cancer patients

作者：Dasgupta Santanu^*; Pal Prodipto; Mukhopadhyay Nitai D; Fu Yumei; Ratovitski Edward A; Moon Chul So; Hoque Mohammad Obaidul; Fisher Paul B; Trink Barry

来源：International Journal of Oncology, 2012, 41(4): 1405-1410.

DOI：10.3892/ijo.2012.1567

• colorectal cancer
• PIGK
• 3%26apos
• UTR
• single nucleotide polymorphism

Colorectal cancer (CRC) represents one of the highest incidences of cancers worldwide. Phosphatidylinositol glycan, class K (PICK), is a crucial member of the glycosylphosphatidylinositol transamidase (GPIT) protein complex that attaches a diverse group of macromolecules to the plasma membrane of eukaryotes. However, the precise role of PICK in tumorigenesis remains largely unknown. Recently, we reported low expression of PICK 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 PICK 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 -%26gt; C/G or G/G; rs1048575) in the 3%26apos;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%26lt;0.002) expression of PICK 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 PICK genotype (SNP-1048575) and corresponding protein expression. We observed altered alleles (C/G or G/G) and corresponding low PICK 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%26apos;s t-test, p%26lt;0.002) PIGK protein expression compared to the Hep3B line carrying the ancestral (C/C) alleles. To examine the exogenous PICK 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 PICK protein in HepG2 (C/C) cells, but no PICK 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 PICK expression in CRC/HCC patients and also suggest a possible association between altered PICK expression and disease susceptibility.

• 出版日期2012-10