肝癌干细胞的扩散和转移：揭示 NRCAM 在肝细胞癌中的作用。
Liver cancer stem cell dissemination and metastasis: uncovering the role of NRCAM in hepatocellular carcinoma.
机构信息
Center of Infectious Diseases, West China Hospital of Sichuan University, 37 GuoXue Lane, Chengdu, 610041, Sichuan Province, China.
Division of Infectious Diseases, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, China.
出版信息
J Exp Clin Cancer Res. 2023 Nov 22;42(1):311. doi: 10.1186/s13046-023-02893-w.
BACKGROUND
Liver cancer stem cells (LCSCs) play an important role in hepatocellular carcinoma (HCC), but the mechanisms that link LCSCs to HCC metastasis remain largely unknown. This study aims to reveal the contributions of NRCAM to LCSC function and HCC metastasis, and further explore its mechanism in detail.
METHODS
117 HCC and 29 non-HCC patients with focal liver lesions were collected and analyzed to assess the association between NRCAM and HCC metastasis. Single-cell RNA sequencing (scRNA-seq) was used to explore the biological characteristics of cells with high NRCAM expression in metastatic HCC. The role and mechanism of NRCAM in LCSC dissemination and metastasis was explored in vitro and in vivo using MYC-driven LCSC organoids from murine liver cells.
RESULTS
Serum NRCAM is associated with HCC metastasis and poor prognosis. A scRNA-seq analysis identified that NRCAM was highly expressed in LCSCs with MYC activation in metastatic HCC. Moreover, NRCAM facilitated LCSC migration and invasion, which was confirmed in MYC-driven LCSC organoids. The in vivo tumor allografts demonstrated that NRCAM mediated intra-hepatic/lung HCC metastasis by enhancing the ability of LCSCs to escape from tumors into the bloodstream. Nrcam expression inhibition in LCSCs blocked HCC metastasis. Mechanistically, NRCAM activated epithelial-mesenchymal transition (EMT) and metastasis-related matrix metalloproteinases (MMPs) through the MACF1 mediated β-catenin signaling pathway in LCSCs.
CONCLUSIONS
LCSCs typified by high NRCAM expression have a strong ability to invade and migrate, which is an important factor leading to HCC metastasis.
背景
肝癌干细胞（LCSCs）在肝细胞癌（HCC）中发挥重要作用，但将 LCSCs 与 HCC 转移联系起来的机制在很大程度上尚不清楚。本研究旨在揭示 NRCAM 对 LCSC 功能和 HCC 转移的贡献，并进一步详细探讨其机制。
方法
收集并分析了 117 例 HCC 和 29 例局灶性肝病变非 HCC 患者的样本，以评估 NRCAM 与 HCC 转移之间的关联。单细胞 RNA 测序（scRNA-seq）用于探索转移性 HCC 中高 NRCAM 表达细胞的生物学特征。使用 MYC 驱动的来自鼠肝细胞的 LCSC 类器官，在体外和体内研究 NRCAM 在 LCSC 扩散和转移中的作用和机制。
结果
血清 NRCAM 与 HCC 转移和不良预后相关。scRNA-seq 分析表明，在转移性 HCC 中，具有 MYC 激活的 LCSCs 中 NRCAM 高表达。此外，NRCAM 促进了 LCSC 的迁移和侵袭，这在 MYC 驱动的 LCSC 类器官中得到了证实。体内肿瘤移植实验表明，NRCAM 通过增强 LCSC 逃离肿瘤进入血液的能力，介导肝内/肺 HCC 转移。LCSC 中 Nrcam 表达的抑制阻断了 HCC 的转移。在机制上，NRCAM 通过 MACF1 介导的 β-catenin 信号通路在 LCSC 中激活上皮-间充质转化（EMT）和转移相关的基质金属蛋白酶（MMPs）。
结论
高 NRCAM 表达的 LCSC 具有较强的侵袭和迁移能力，是导致 HCC 转移的重要因素。
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