RECK functions as a metastasis suppressor in CCA; upregulation of RECK expression could provide a potential therapy to improve the prognosis of this type of cancer.

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.

TP53 is the most common gene mutated in human cancers, including in cholangiocarcinoma (CCA). The gain-of-function properties of p53 variants are often involved in cancer progression. The present study demonstrated that a truncated del p53 variant, del p53 M213 , exhibited gain-of-function properties and was highly expressed in the invasive liver fluke Opisthorchis viverrini-associated CCA cell line, KKU-M213. The del p53 M213 variant lacked exons 7-9 and contained a V31I substitution (p53-p72-Δ225-331-V31I). Stably transfected p53-null human non-small cell lung H1299 cells exhibited a del p53 M213 localization in both the cell cytosol and nucleus. Del p53 M213 lacked anti-growth functions, and instead enhanced migration and invasiveness. In addition, this p53 variant downregulated claudin-1 expression and promoted Cdc42 activation, consistent with the roles of claudin-1 and Cdc42 in inhibiting cell-cell dissociation and promoting cell migration, respectively. On the whole, although del p53 M213 is an important driver of cancer cell migration and invasiveness, other properties related to its novel gain-of-function properties require further investigation in order to develop effective treatment strategies for cancers bearing this truncated TP53 allele.

Cholangiocarcinoma (CCA), a devastating epithelial tumor arising in bile ducts with dismal prognosis and high mortality rate, has the highest worldwide incidence in Northeastern Thailand, raising a serious health public concern to the country. Due to a desmoplastic nature of CCA, understanding CCA cell-matrix interaction is necessitated.Here, an in silico analysis using two RNA-sequencing (Pan-Cancer Analysis of Whole Genomes and The Cancer Genome Atlas) databases and ten microarray datasets from the Gene Expression Omnibus database, was utilized to compare the mRNA expression of 19 genes of laminins' cognate receptors between CCA and adjacent noncancerous tissues. The results were further validated in tissues of Thai patients using qPCR analysis. Bioinformatics analyses revealed that there were five common dysregulated genes in the three transcriptomic databases, in which four were upregulated genes (ITGAV, ITGA2, ITGB1, and ITGB4), and one was downregulated gene (SDC2). Of these differentially expressed genes, qPCR analysis confirmed the elevated mRNA expression of ITGB4 encoding integrin β4 in 97% of the CCA cases and pinpointing the ITGB4 as a potential diagnostic biomarker for CCA.