Yang Chun-Yuan, Guo Li-Mei, Li Yang, Wang Guang-Xi, Tang Xiao-Wei, Zhang Qiu-Lu, Zhang Ling-Fu, Luo Jian-Yuan
Department of Pathology, Institute of Systems Biomedicine, School of Basic Medical Sciences Peking University, Peking University Third Hospital, Peking University Health Science Center, Beijing 100191, China.
Department of General Surgery, Peking University Third Hospital, Beijing 100191, China.
World J Gastrointest Oncol. 2024 Apr 15;16(4):1344-1360. doi: 10.4251/wjgo.v16.i4.1344.
Cholangiocarcinoma (CCA) is a highly malignant cancer, characterized by frequent mucin overexpression. has been identified as a critical oncogene in the progression of CCA. However, the comprehensive understanding of how the mucin family influences CCA progression and prognosis is still incomplete.
To investigate the functions of mucins on the progression of CCA and to establish a risk evaluation formula for stratifying CCA patients.
Single-cell RNA sequencing data from 14 CCA samples were employed for elucidating the roles of mucins, complemented by bioinformatic analyses. Subsequent validations were conducted through spatial transcriptomics and immunohistochemistry. The construction of a risk evaluation model utilized the least absolute shrinkage and selection operator regression algorithm, which was further confirmed by independent cohorts and diverse data types.
CCA tumor cells with elevated levels of and showed activated nucleotide metabolic pathways and increased invasiveness. -high cells were found to promote CCA progression through WNT signaling. -high cells exhibited robust cellular oxidation activities, leading to resistance against antitumoral treatments. -high cells were observed to secret chemokines, recruiting and transforming macrophages into the M2-polarized state, thereby suppressing antitumor immunity. -high cells were found to promote tumor progression through interleukin-1/nuclear factor kappa-light-chain-enhancer of activated B cells signaling upon interaction with neutrophils. Utilizing the expression levels of these mucins, a risk factor evaluation formula for CCA was developed and validated across multiple cohorts. CCA samples with higher risk factors exhibited stronger metastatic potential, chemotherapy resistance, and poorer prognosis.
Our study elucidates the functional mechanisms through which mucins contribute to CCA development, and provides tools for risk stratification in CCA.
胆管癌（CCA）是一种高度恶性的癌症，其特征是粘蛋白频繁过表达。已被确定为CCA进展中的关键致癌基因。然而，对粘蛋白家族如何影响CCA进展和预后的全面理解仍不完整。
研究粘蛋白在CCA进展中的作用，并建立一个用于对CCA患者进行分层的风险评估公式。
使用来自14个CCA样本的单细胞RNA测序数据来阐明粘蛋白的作用，并辅以生物信息学分析。随后通过空间转录组学和免疫组织化学进行验证。风险评估模型的构建采用最小绝对收缩和选择算子回归算法，并通过独立队列和不同数据类型进一步确认。
和水平升高的CCA肿瘤细胞显示出激活的核苷酸代谢途径和增加的侵袭性。发现高细胞通过WNT信号通路促进CCA进展。高细胞表现出强大的细胞氧化活性，导致对抗肿瘤治疗的抗性。观察到高细胞分泌趋化因子，将巨噬细胞募集并转化为M2极化状态，从而抑制抗肿瘤免疫。发现高细胞在与中性粒细胞相互作用时通过白细胞介素-1/活化B细胞核因子κ-轻链增强子信号通路促进肿瘤进展。利用这些粘蛋白的表达水平，开发了一个CCA风险因素评估公式，并在多个队列中进行了验证。具有较高风险因素的CCA样本表现出更强的转移潜力、化疗抗性和更差的预后。
我们的研究阐明了粘蛋白促进CCA发展的功能机制，并为CCA的风险分层提供了工具。
