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CD168⁺ macrophages promote hepatocellular carcinoma tumor stemness and progression through TOP2A/β-catenin/YAP1 axis.

ABSTRACT: Liver cancer stem-like cells (LCSCs) are the main cause of heterogeneity and poor prognosis in hepatocellular carcinoma (HCC). In this study, we aimed to explore the origin of LCSCs and the role of the TOP2A/β-catenin/YAP1 axis in tumor stemness and progression. Using single-cell RNA-seq analysis, we identified TOP2A⁺CENPF⁺ LCSCs, which were mainly regulated by CD168⁺ M2-like macrophages. Furthermore, spatial location analysis and fluorescent staining confirmed that LCSCs were enriched at tumor margins, constituting the spatial heterogeneity of HCC. Mechanistically, TOP2A competitively binds to β-catenin, leading to disassociation of β-catenin from YAP1, promoting HCC stemness and overgrowth. Our study provides valuable insights into the spatial transcriptome heterogeneity of the HCC microenvironment and the critical role of TOP2A/β-catenin/YAP1 axis in HCC stemness and progression.

SUBMITTER: Zhao HC

PROVIDER: S-EPMC10238939 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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CD168+ macrophages promote hepatocellular carcinoma tumor stemness and progression through TOP2A/β-catenin/YAP1 axis.

Zhao Hai-Chao HC Chen Chang-Zhou CZ Tian Yan-Zhang YZ Song Huang-Qin HQ Wang Xiao-Xiao XX Li Yan-Jun YJ He Jie-Feng JF Zhao Hao-Liang HL

iScience 20230512 6

Liver cancer stem-like cells (LCSCs) are the main cause of heterogeneity and poor prognosis in hepatocellular carcinoma (HCC). In this study, we aimed to explore the origin of LCSCs and the role of the TOP2A/β-catenin/YAP1 axis in tumor stemness and progression. Using single-cell RNA-seq analysis, we identified TOP2A+CENPF+ LCSCs, which were mainly regulated by CD168+ M2-like macrophages. Furthermore, spatial location analysis and fluorescent ...[more]

PMID: 37275516

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide, and cancer stem cell is responsible for the poor clinical outcome of NSCLC. Previous reports indicated that long noncoding RNAs (lncRNAs) play important roles in maintaining cancer stemness, however, the underlying mechanisms remain unclear. This study investigates the role of ASAP1 Intronic Transcript 1 (ASAP1-IT1) in cancer cell stemness of NSCLC.MethodsThe expression of ASAP1-IT1, microRNA-509-3p (miR-509-3p) and apoptosis-/stemness-related genes was analyzed by qRT-PCR in NSCLC tissues, cancer cells and spheres of cancer stem cells. Knockdown of ASAP1-IT1 or overexpression of miR-509-3p in NSCLC cells by infection or transfection of respective plasmids. Sphere formation and colony formation were used to detect NSCLC stem cell-like properties and tumor growth in vitro. Luciferase reporter assays, RNA immunoprecitation (RIP) and qRT-PCR assays were used to analyze the interaction between lncRNA and miRNA. The expression of expression of regulated genes of ASAP1-IT1/miR-509-3p axis was evaluated by qRT-PCR and Western blot. The NSCLC xenograft mouse model was used to validate the role of ASAP1-IT1 in NSCLC stemness and tumor growth in vivo.ResultsASAP1-IT1 was up-regulated in NSCLC tissues, cancer cells, and in spheres of A549-derived cancer stem cells. Downregulation of ASAP1-IT1 or overexpression of miR-509-3p significantly decreased cell colony formation and stem cell-like properties of A549-dereived stem cells with decreased expression of stem cell biomarkers SOX2, CD34, and CD133, and suppressing the expression of cell growth-related genes, Cyclin A1, Cyclin B1, and PCNA. Furthermore, knockdown of ASAP1-IT1 or overexpression of miR-509-3p repressed tumor growth in nude mice via reducing expression of tumorigenic genes. ASAP1-IT1 was found to interact with miR-509-3p. Moreover, overexpression of ASAP1-IT1 blocked the inhibition by miR-509-3p on stem cell-like properties and cell growth of A549-dereived stem cells both in vitro and in vivo. Finally, the level of YAP1 was regulated by ASAP1-IT1 and miR-509-3p.ConclusionsYAP1-involved ASAP1-IT1/miR-509-3p axis promoted NSCLC progression by regulating cancer cell stemness, and targeting this signaling pathway could be is a promising therapeutic strategy to overcome NSCLC stemness.

Dataset Information

CD168⁺ macrophages promote hepatocellular carcinoma tumor stemness and progression through TOP2A/β-catenin/YAP1 axis.

Publications

<i>CD168</i><sup>+</sup> macrophages promote hepatocellular carcinoma tumor stemness and progression through <i>TOP2A</i>/β-catenin/<i>YAP1</i> axis.

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