Evaluation of p53 and Its Target Gene Expression as Potential Biomarkers of Cholangiocarcinoma in Thai Patients

BACKGROUND: Cholangiocarcinoma (CCA), a common cancer in northeastern Thailand, is a severe disease with poor prognosis and short survival time following diagnosis. DNA damage in CCA is believed to be caused by liver fluke infection in combination with exposure to carcinogens. p53, a tumor suppressor, is the most mutated gene in human cancers including liver fluke-associated CCA. Hence, expression patterns of p53 and its target genes may be useful for diagnosis and/or prognosis of CCA patients. METHODS: Differential mRNA expression of p53 and its target genes, namely, FUCA1, ICAM2 MDM2, p21, PAI-1, S100A9, and WIP1 in CCA tissue samples (n = 30) relative to matched adjacent non-tumor tissues was determined by quantitative RT-PCR and compared to clinicopathological features. Level of p53 protein was determined by immunohistochemistry and correlated with the expression of its target genes. RESULTS: Immunohistochemistry showed elevation of p53 protein level in 77% of the cases, while RT-PCR showed downregulation of p53 mRNA and its seven target genes in 23% and 47-97% of the samples. PAI-1 was down-regulated in almost all CCA samples, thus highlighting it as a potential diagnostic marker for CCA. However, no significant clinical associations were found except for down-regulation of WIP1 that was significantly correlated with non-papillary type tissue (p-value = 0.001) and with high p53 protein level (p-value = 0.007). CONCLUSION: Our results demonstrated statistically significant association between down-regulation of WIP1 with non-papillary type and with high p53 protein level, and PAI-1 was down-regulated in almost all CCA. Therefore, expression level of WIP1 and PAI-1 may be useful for predicting p53 functional status and as a potential diagnostic marker of CCA, respectively.