Lenvatinib‐resistant hepatocellular carcinoma promotes malignant potential of tumor‐associated macrophages via exosomal miR‐301a‐3p

IF 2.9 4区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Annals of Gastroenterological Surgery Pub Date : 2024-05-13 DOI:10.1002/ags3.12814
Yuhei Waki, Y. Morine, Yu Saito, H. Teraoku, S. Yamada, T. Ikemoto, Tatsuya Tominaga, M. Shimada
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Abstract

The interactions between cancer cells and tumor‐associated macrophages (TAMs) via microRNAs (miRNAs) play crucial roles in malignant potential and drug resistance. However, it remains unclear how lenvatinib‐resistant hepatocellular carcinoma (LR HCC) promotes TAM tumor biology. Here we investigated the crosstalk between LR HCC cells and TAMs for cancer progression and lenvatinib resistance, focusing on an exosomal miRNA.We used two bioinformatics software programs to identify miRNAs that target PTEN in gastrointestinal cancers, then investigated exosomal miRNA expression in LR HCC conditioned medium (CM). After modifying TAMs with LR HCC CM (LR TAM), macrophage phenotype and PTEN‐Nrf2 signaling pathway component expression were analyzed in LR TAMs. The malignant potential and drug resistance were investigated in naïve HCC cells cultured with LR TAM CM.LR HCC cells highly induced M2‐like properties in macrophages compared with naïve HCC cells. Exosomal miR‐301a‐3p expression was increased in LR HCC CM, with higher activation of the PTEN/PI3K/GSK3β/Nrf2 signaling pathway in LR TAMs. Naïve HCC cells were educated with LR TAM CM to promote malignant potential and lenvatinib resistance. Inhibition of exosomal miR‐301a‐3p prevented the malignant potential of LR TAMs. Activation of Nrf2 signaling by LR HCC cell‐derived exosomal miR‐301a‐3p skewed the transformation of macrophages to the M2 phenotype.Our study provides new findings on the role of miR‐301a‐3p, suggesting it is a promising therapeutic target to improve HCC lenvatinib resistance.
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耐伦伐替尼肝细胞癌通过外泌体miR-301a-3p促进肿瘤相关巨噬细胞的恶性潜能
癌细胞与肿瘤相关巨噬细胞(TAMs)之间通过微RNAs(miRNAs)进行的相互作用在恶性潜能和耐药性方面起着至关重要的作用。然而,目前仍不清楚来伐替尼耐药肝细胞癌(LR HCC)是如何促进TAM肿瘤生物学的。在这里,我们研究了LR HCC细胞和TAMs之间的串联作用,以研究癌症进展和来伐替尼耐药性,重点是一种外泌体miRNA。我们使用了两种生物信息学软件来识别胃肠道癌症中靶向PTEN的miRNA,然后研究了LR HCC条件培养基(CM)中外泌体miRNA的表达。用LR HCC CM(LR TAM)改造TAM后,分析了LR TAM中巨噬细胞表型和PTEN-Nrf2信号通路成分的表达。与天真HCC细胞相比,LR HCC细胞高度诱导巨噬细胞的M2样特性。LR HCC CM中外泌体miR-301a-3p的表达增加,LR TAMs中PTEN/PI3K/GSK3β/Nrf2信号通路的激活程度更高。用LR TAM CM培养新发HCC细胞可促进恶性潜能和来伐替尼耐药。抑制外泌体miR-301a-3p可阻止LR TAMs的恶性潜能。我们的研究提供了关于miR-301a-3p作用的新发现,表明它是改善HCC来伐替尼耐药的一个有希望的治疗靶点。
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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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