Abstract：
UNASSIGNED: Microvascular invasion (MVI) is a major unfavorable prognostic factor for intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). However, the intervention and preoperative prediction for MVI remain clinical challenges due to the absent precise mechanism and molecular marker(s). Herein, we aimed to investigate the mechanisms underlying vascular invasion that can be applied to clinical intervention for MVI in HCC.
UNASSIGNED: The histopathologic characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including coculture modeling, RNA-sequencing, and proteomic analysis, were used to investigate MVI-related genes and mechanisms.
UNASSIGNED: IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSC) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSC activation and disruption of the HSC-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small-interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC.
UNASSIGNED: Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI.
UNASSIGNED: The histopathologic characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including coculture modeling, RNA-sequencing, and proteomic analysis, were used to investigate MVI-related genes and mechanisms.
UNASSIGNED: IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSC) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSC activation and disruption of the HSC-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small-interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC.
UNASSIGNED: Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI.
摘要：
■微血管侵犯（MVI）是肝细胞癌（HCC）肝内转移和术后复发的主要不良预后因素。然而,由于缺乏确切的机制和分子标志物,因此MVI的干预和术前预测仍是临床挑战.在这里，我们的目的是研究血管侵犯的潜在机制，可应用于HCCMVI的临床干预。
■使用多重免疫荧光染色分析临床MVI+/HCC标本的组织病理学特征。肝脏原位异种移植小鼠模型和人类患者来源的HCC细胞系的机制实验，包括共文化建模，RNA测序，和蛋白质组学分析，用于研究MVI相关基因和机制。
■IQGAP3过表达与HCC的MVI状态和生存率降低显著相关。IQGAP3的上调促进MVI-HCC细胞采用浸润性血管共生长模式，并通过诱导活化的肝星状细胞（HSC）从内皮脱离而进入毛细血管。机械上,IQGAP3过表达通过双重机制促进HCC血管侵袭，其中IQGAP3通过上调多种细胞因子诱导HSC激活和HSC-内皮相互作用的破坏，并通过维持GTPaseRac1活性重塑细胞骨架来增强MVI-HCC细胞的跨内皮迁移。重要的是,靶向IQGAP3的小干扰RNA纳米颗粒的全身递送破坏了浸润血管共生长模式并降低了HCC的MVI。
■我们的结果揭示了IQGAP3介导的肝癌微血管侵袭的潜在机制，并为开发治疗MVIHCC的治疗策略提供了潜在的目标。
■使用多重免疫荧光染色分析临床MVI+/HCC标本的组织病理学特征。肝脏原位异种移植小鼠模型和人类患者来源的HCC细胞系的机制实验，包括共文化建模，RNA测序，和蛋白质组学分析，用于研究MVI相关基因和机制。
■IQGAP3过表达与HCC的MVI状态和生存率降低显著相关。IQGAP3的上调促进MVI-HCC细胞采用浸润性血管共生长模式，并通过诱导活化的肝星状细胞（HSC）从内皮脱离而进入毛细血管。机械上,IQGAP3过表达通过双重机制促进HCC血管侵袭，其中IQGAP3通过上调多种细胞因子诱导HSC激活和HSC-内皮相互作用的破坏，并通过维持GTPaseRac1活性重塑细胞骨架来增强MVI-HCC细胞的跨内皮迁移。重要的是,靶向IQGAP3的小干扰RNA纳米颗粒的全身递送破坏了浸润血管共生长模式并降低了HCC的MVI。
■我们的结果揭示了IQGAP3介导的肝癌微血管侵袭的潜在机制，并为开发治疗MVIHCC的治疗策略提供了潜在的目标。
