Computational analyses to reveal the key determinants of the high malignancy level of cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: Cholangiocarcinoma (CHOL) is a rare and highly aggressive cancer that originates in the bile duct; it has an average five-year survival rate of 9%, which makes it the cancer with the lowest survival rate among all 33 cancer types in the cancer genome atlas (TCGA) Program. The aim of this study is to elucidate the key determinants of the high malignancy level of CHOL through computational and cell-based experimental approaches and, particularly, to investigate how bile acids (BAs) influence CHOL's propensity to metastasize. METHODS: Our study analyzed the transcriptomic data from 1835 tissue samples of 7 digestive system cancer types in the TCGA database and compared them with those of 330 control tissue samples. Multiple cellular and molecular factors were considered in the study, including the level of hypoxia, level of immune cell infiltration, degree of cellular dedifferentiation, and level of sialic acid (SA) accumulation on the surface of cancer cells. Using these factors, we developed a multivariable regression model for the five-year survival rate, as reported by the Surveillance, Epidemiology, and End Results (SEER) Program reports, and analyzed how BA biology influences a few of these factors and causes CHOL to have a high malignancy level. RESULTS: CHOL exhibited the highest level of SA accumulation and B-cell infiltration among all cancer types studied. BAs inhibit the cell cycle progression through the receptor GPBAR1, thereby limiting the rate of nucleotide biosynthesis-which in turn forces the cells to increase SA biosynthesis in order to maintain the intracellular pH at a stable level-thereby driving cell migration and metastasis, as established in our previous study. CONCLUSIONS: BAs are the key contributors to the lowest five-year survival rate of CHOL among the seven cancer types studied here. This finding not only reveals the molecular mechanisms underlying the high malignancy level of CHOL but also provides a new potential target for the diagnosis and treatment of CHOL.