Li Xuan, Liu Aoran, Mu Xuechen, Wang Zhihang, Xiao Jun, Qu Yinwei, Huang Zhenyu, Zhang Ye, Xu Ying
Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, College of Computer Science and Technology, Jilin University, Changchun 130012, Jilin Province, China.
School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong Province, China.
J Transl Int Med. 2025 Jan 10;12(6):602-617. doi: 10.1515/jtim-2024-0033. eCollection 2024 Dec.
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.
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.
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 , 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.
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.
胆管癌（CHOL）是一种起源于胆管的罕见且侵袭性很强的癌症；其平均五年生存率为9%，这使其成为癌症基因组图谱（TCGA）计划中33种癌症类型里生存率最低的癌症。本研究的目的是通过计算和基于细胞的实验方法阐明胆管癌高恶性水平的关键决定因素，特别是研究胆汁酸（BAs）如何影响胆管癌的转移倾向。
我们的研究分析了TCGA数据库中7种消化系统癌症类型的1835个组织样本的转录组数据，并将其与330个对照组织样本的数据进行比较。研究中考虑了多个细胞和分子因素，包括缺氧水平、免疫细胞浸润水平、细胞去分化程度以及癌细胞表面唾液酸（SA）积累水平。利用这些因素，我们根据监测、流行病学和最终结果（SEER）计划报告中所报道的五年生存率建立了一个多变量回归模型，并分析了胆汁酸生物学如何影响其中一些因素并导致胆管癌具有高恶性水平。
在所有研究的癌症类型中胆管癌表现出最高水平的唾液酸积累和B细胞浸润。如我们之前的研究所证实，胆汁酸通过受体抑制细胞周期进程，从而限制核苷酸生物合成速率，这反过来迫使细胞增加唾液酸生物合成以将细胞内pH维持在稳定水平，进而驱动细胞迁移和转移。
胆汁酸是此处研究的七种癌症类型中胆管癌五年生存率最低的关键因素。这一发现不仅揭示了胆管癌高恶性水平的分子机制，还为胆管癌的诊断和治疗提供了一个新的潜在靶点。
