Quercetin inhibits endothelial & hepatocellular carcinoma cell crosstalk via reducing extracellular vesicle-mediated VEGFR2 mRNA transfer.

IF 3 2区 医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Carcinogenesis Pub Date : 2024-11-01 Epub Date: 2024-08-22 DOI:10.1002/mc.23807
Wei Xiong, Bo Zheng, Di Liu, Mo Pu, Shijie Zhou, Ying Deng
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Abstract

This study aims to investigate the regulatory effects of quercetin extracellular vesicles (EVs)-mediated expression of vascular endothelial growth factor receptor 2 (VEGFR2) in hepatocellular carcinoma (HCC)-derived circulating tumor cells (CTCs) and the underlying mechanisms. CTCs were isolated from patients with pathologically diagnosed HCC, with VEGFR2 expression visualized by fluorescence in situ hybridization (FISH). The human HCC cell line Huh-7 and SK-HEP-1 were used for in vitro studies to assess EVs uptake, VEGFR2 mRNA transfer, invasion, migration, cancer stem cell (CSC) properties, and VEGF secretion. Results showed that VEGFR2 mRNA was commonly expressed in HCC-CTCs, with a higher incidence in biphenotypic CTCs. Its expression was limited in HCC cell lines, but present in certain liver cells. In vitro experiments confirmed that VEGFR2 mRNA could be transferred to HCC cells via EVs from primary tumor endothelial cells (PTECs), which was impaired by quercetin treatment. Quercetin significantly reduced VEGFR2 mRNA and protein expression in HCC cells, weakened their invasive and metastatic capacities, and diminished VEGFR2-mediated CSC properties. In vivo, quercetin reduced VEGF secretion, impaired angiogenesis, slowed tumor growth, and decreased the number and proportion of VEGFR2-positive CTCs. In summary, VEGFR2 mRNA is present in HCC-CTCs, potentially sourced from PTECs-derived EVs. Quercetin effectively inhibits VEGFR2 expression, impacting HCC cell invasion, metastasis, and CSC characteristics. Besides, it reduces VEGFR2-positive CTCs in vivo. These effects support its therapeutic potential in HCC treatment by targeting the angiogenesis and tumor dissemination pathway.

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槲皮素通过减少细胞外囊泡介导的 VEGFR2 mRNA 转移,抑制内皮细胞和肝细胞癌细胞的串联。
本研究旨在探讨槲皮素细胞外囊泡(EVs)介导的血管内皮生长因子受体2(VEGFR2)在肝细胞癌(HCC)产生的循环肿瘤细胞(CTCs)中的表达调控作用及其内在机制。CTCs 从病理诊断为 HCC 的患者中分离出来,通过荧光原位杂交(FISH)检测 VEGFR2 的表达。人类 HCC 细胞系 Huh-7 和 SK-HEP-1 被用于体外研究,以评估 EVs 吸收、VEGFR2 mRNA 转移、侵袭、迁移、癌症干细胞(CSC)特性和 VEGF 分泌。结果表明,VEGFR2 mRNA 在 HCC-CTCs 中普遍表达,在双型 CTCs 中表达率更高。它在 HCC 细胞系中的表达有限,但在某些肝细胞中存在。体外实验证实,VEGFR2 mRNA可通过原发性肿瘤内皮细胞(PTECs)的EVs转移到HCC细胞中,而槲皮素处理可抑制这种转移。槲皮素能明显降低HCC细胞中VEGFR2 mRNA和蛋白的表达,削弱其侵袭和转移能力,并降低VEGFR2介导的CSC特性。在体内,槲皮素可减少血管内皮生长因子的分泌,阻碍血管生成,减缓肿瘤生长,并减少 VEGFR2 阳性 CTC 的数量和比例。总之,HCC-CTCs 中存在 VEGFR2 mRNA,其来源可能是 PTECs 衍生的 EVs。槲皮素能有效抑制 VEGFR2 的表达,从而影响 HCC 细胞的侵袭、转移和 CSC 特性。此外,它还能减少体内 VEGFR2 阳性的 CTC。这些作用支持了槲皮素通过靶向血管生成和肿瘤扩散途径治疗 HCC 的潜力。
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来源期刊
Molecular Carcinogenesis
Molecular Carcinogenesis 医学-生化与分子生物学
CiteScore
7.30
自引率
2.20%
发文量
112
审稿时长
2 months
期刊介绍: Molecular Carcinogenesis publishes articles describing discoveries in basic and clinical science of the mechanisms involved in chemical-, environmental-, physical (e.g., radiation, trauma)-, infection and inflammation-associated cancer development, basic mechanisms of cancer prevention and therapy, the function of oncogenes and tumors suppressors, and the role of biomarkers for cancer risk prediction, molecular diagnosis and prognosis.
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