Waki Yuhei, Morine Yuji, Saito Yu, Teraoku Hiroki, Yamada Shinichiro, Ikemoto Tetsuya, Tominaga Tatsuya, Shimada Mitsuo
Department of Digestive and Transplant Surgery Tokushima University Tokushima Japan.
Department of Bioanalytical Technology Tokushima University Tokushima Japan.
Ann Gastroenterol Surg. 2024 May 13;8(6):1084-1095. doi: 10.1002/ags3.12814. eCollection 2024 Nov.
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.
癌细胞与肿瘤相关巨噬细胞（TAM）通过微小RNA（miRNA）相互作用在恶性潜能和耐药性方面起着关键作用。然而，乐伐替尼耐药的肝细胞癌（LR HCC）如何促进TAM肿瘤生物学仍不清楚。在此，我们研究了LR HCC细胞与TAM之间关于癌症进展和乐伐替尼耐药性的相互作用，重点关注外泌体miRNA。
我们使用两个生物信息学软件程序来鉴定胃肠道癌症中靶向PTEN的miRNA，然后研究LR HCC条件培养基（CM）中外泌体miRNA的表达。在用LR HCC CM修饰TAM（LR TAM）后，分析LR TAM中的巨噬细胞表型和PTEN-Nrf2信号通路成分表达。在用LR TAM CM培养的原始HCC细胞中研究其恶性潜能和耐药性。
与原始HCC细胞相比，LR HCC细胞在巨噬细胞中高度诱导M2样特性。LR HCC CM中外泌体miR-301a-3p表达增加，LR TAM中PTEN/PI3K/GSK3β/Nrf2信号通路的激活更高。原始HCC细胞用LR TAM CM处理后促进了恶性潜能和乐伐替尼耐药性。抑制外泌体miR-301a-3p可阻止LR TAM的恶性潜能。LR HCC细胞衍生的外泌体miR-301a-3p激活Nrf2信号通路使巨噬细胞向M2表型转化。
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乐伐替尼耐药性的一个有前景的治疗靶点。
