Exosomal miR-125b Exerts Anti-Metastatic Properties and Predicts Early Metastasis of Hepatocellular Carcinoma

Abstract

Background & AimsCancer metastasis is responsible for the majority of cancer-related deaths. Exosomal miRNAs have emerged as promising biomarkers for cancer, serving as signaling molecules that can regulate tumor growth and metastasis. This study examined circulating exosomal miRNAs that could predict hepatocellular carcinoma (HCC) metastasis.MethodsExosomal miRNA was measured by quantitative real-time PCR (qRT-PCR) in a large set of patients (n = 284). To investigate the role of exosomal miRNA in HCC, we performed a series of in vitro tests, such as exosome labeling, qRT-PCR, reverse transcription PCR, wound healing assay, transwell assay, and Western blot assay.ResultsExosomal miR-125b was drastically downregulated in HCC patients with metastasis than in those without metastasis. In vitro, we observed the uptake of miR-125b by exosome in recipient cells. Exosome-mediated miR-125b significantly inhibited migration and invasion abilities and downregulated the mRNA expressions of MMP-2, MMP-9, and MMP-14 in recipient cells via intercellular communication. Further investigation revealed that miR-125b suppressed SMAD2 protein expression in recipient cells by binding to its 3′ untranslated regions. Exosome-mediated miR-125b transfer also disrupted TGF-β1–induced epithelial–mesenchymal transition and TGF-β1/SMAD signaling pathway in recipient cells by leading to a decrease of SMAD2 protein expression. Moreover, exosomal miR-125b was downregulated after metastasis compared with that at baseline in patients with serial measurements before and after metastasis.ConclusionsThe results imply that exosome-mediated miR-125b exerts anti-metastatic properties in HCC. These findings highlight that circulating exosomal miR-125b might represent a reliable biomarker with diagnostic and therapeutic implications for extrahepatic metastasis from HCC.

Current Perspectives on the Unique Roles of Exosomes in Drug Resistance of Hepatocellular Carcinoma

“…Hisakane et al 84 revealed that miR-210-3p was upregulated in exosomes isolated from osimertinib-resistant HCC827, and their study found that exosomal miR-210-3p may promote EMT and induce resistance to osimertinib in HCC827 cells (a type of lung cancer cell line). Conversely, Kim et al 85 revealed that exosome-mediated miR-125b transfer disrupted TGF-β1-induced EMT and TGF-β1/SMAD signaling pathway in recipient cells via decreasing SMAD2 protein expression. In addition, exosomal miR-125b expression was downregulated after metastasis.…”

“… 24 Theoretically, these studies provide more accurate information for predicting the treatment response of HCC. Kim et al 85 believed that exosomal miR-125b may be a reliable biomarker for the diagnosis and evaluation of extrahepatic metastasis of HCC. Zhu et al 91 established a prognosis and recurrence risk prediction model, which presented a significant predictive performance, based on two exosomal genes (MYL6B and THOC2).…”

Role of exosomes in hepatocellular carcinoma and the regulation of traditional Chinese medicine

“…Exosomal miR-125b exerts an anti-metastatic effect through interfering TGF-β1-induced epithelial-mesenchymal transition (EMT) and therefore drastically downregulated miR-125b predicts early metastasis of HCC (Kim et al, 2021). Circulating exosomal miR-1307-5p promotes metastasis and helps predict metastasis in HCC through targeting the tumor suppressor genes SEC14L2 and ENG to promote EMT (Eun et al, 2020).…”

“…Interestingly, the plasma exosomal miRNAs could also serve as potential metastasis-related biomarkers for HCC ( Huang et al, 2021 ; Kim et al, 2021 ). Huang et al ( Huang et al, 2021 ) showed a total of 32 differentially expressed miRNAs in the plasma exosomes of patients with metastatic HCC compared with those without metastasis and the combination of three miRNAs (miR-18a, miR-27a and miR-20b) could discriminate metastatic HCC from non-metastatic HCC.…”

Roles of small extracellular vesicles in the development, diagnosis and possible treatment strategies for hepatocellular carcinoma (Review)

“…Apart from their early diagnostic value, sEV cargos may be involved in the prediction of tumor staging and metastasis (144)(145)(146)(147). Exo-miR-1307-5p expression in plasma has been found to be positively associated with tumor stage and progression, while sEVs carrying miR-125b have been shown to possess anti-metastatic features and are indicators of early metastasis in HCC (148)(149)(150). Other sEV cargos can play a similar role in tumor staging or metastasis prediction, and the function of lncRNA ATB, hnRNPH1 and ASMTL-AS1 in this regard has been reported (151)(152)(153).…”