Exosomal circ_0032704 confers sorafenib resistance to hepatocellular carcinoma and contributes to cancer malignant progression by modulating the miR-514a-3p/PD-L1 pathway

IF 2.9 4区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Annals of Gastroenterological Surgery Pub Date : 2024-01-23 DOI:10.1002/ags3.12772
Chengyun Dou, Hongbo Zhu, Xia Xie, Cuiqin Huang, Hui Tan, Chuangjie Cao
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Abstract

Purpose

This study aims to explore the role of circ_0032704 in sorafenib-resistant hepatocellular carcinoma (HCC).

Methods

The expression of circ_0032704, miR-514a-3p, and programmed death-ligand 1 (PD-L1) mRNA was detected by quantitative real-time PCR (qPCR). The expression of multidrug resistant-related proteins, migration/invasion-related proteins, exosome-related proteins, and PD-L1 protein was detected by western blot. Cell viability was detected by CCK-8 assay. Cell proliferation, migration, and invasion were assessed by EdU assay, wound healing assay, and transwell assay. The binding between miR-514a-3p and circ_0032704 or PD-L1 was verified by RIP assay, pull-down assay, and dual-luciferase reporter assay. Cell- or serum-derived exosomes were isolated and identified by TEM and NTA. Xenograft models were established to determine the effect of circ_0032704 on drug resistance in vivo.

Results

Circ_0032704 was overexpressed in sorafenib-resistant HCC tissues and cells. Circ_0032704 knockdown reduced sorafenib resistance in HCC cells and inhibited cell proliferation, migration, and invasion of sorafenib-resistant HCC cells, while these effects were reversed by PD-L1 overexpression. We found that circ_0032704 positively regulated PD-L1 expression via targeting miR-514a-3p. Exosomes with circ_0032704 inhibition reduced sorafenib resistance in HCC cells and inhibited cell proliferation, migration, and invasion of sorafenib-resistant HCC cells. Exosomes with circ_0032704 inhibition also inhibited tumor growth in vivo. The expression of circ_0032704 in exosomes was stable and possessed diagnostic value.

Conclusion

Circ_0032704 enhanced sorafenib resistance in HCC and promoted the malignant development of sorafenib-resistant HCC. Circ_0032704 could be transported by exosomes, and exosomal circ_0032704 had diagnostic value.

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外泌体circ_0032704通过调节miR-514a-3p/PD-L1通路赋予肝细胞癌索拉非尼耐药性并促进癌症恶性进展
本研究旨在探讨circ_0032704在索拉非尼耐药肝细胞癌(HCC)中的作用。研究人员采用实时定量PCR(qPCR)技术检测了circ_0032704、miR-514a-3p和程序性死亡配体1(PD-L1)mRNA的表达。免疫印迹法检测了耐多药相关蛋白、迁移/侵袭相关蛋白、外泌体相关蛋白和 PD-L1 蛋白的表达。通过 CCK-8 检测法检测细胞活力。细胞增殖、迁移和侵袭通过 EdU 试验、伤口愈合试验和透孔试验进行评估。miR-514a-3p 与 circ_0032704 或 PD-L1 之间的结合通过 RIP 试验、牵引试验和双荧光素酶报告器试验进行了验证。通过 TEM 和 NTA 分离并鉴定了细胞或血清来源的外泌体。建立了异种移植模型,以确定 circ_0032704 对体内耐药性的影响。Circ_0032704敲除可降低HCC细胞对索拉非尼的耐药性,抑制索拉非尼耐药HCC细胞的增殖、迁移和侵袭,而PD-L1过表达可逆转这些效应。我们发现,circ_0032704通过靶向miR-514a-3p正向调控PD-L1的表达。抑制circ_0032704的外泌体可降低HCC细胞对索拉非尼的耐药性,并抑制索拉非尼耐药HCC细胞的增殖、迁移和侵袭。抑制 circ_0032704 的外泌体还能抑制体内肿瘤的生长。Circ_0032704增强了HCC对索拉非尼的耐药性,促进了索拉非尼耐药HCC的恶性发展。Circ_0032704可通过外泌体转运,外泌体circ_0032704具有诊断价值。
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来源期刊
Annals of Gastroenterological Surgery
Annals of Gastroenterological Surgery GASTROENTEROLOGY & HEPATOLOGY-
CiteScore
5.30
自引率
11.10%
发文量
98
审稿时长
11 weeks
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