Exosomal miR‐374c‐5p derived from mesenchymal stem cells suppresses epithelial‐mesenchymal transition of hepatocellular carcinoma via the LIMK1‐Wnt/β‐catenin axis

Abstract

Metastasis is a leading cause to treatment failure in hepatocellular carcinoma (HCC) patients. Exosomes act as pivotal mediators in communication between different cells and exert effects on recipient cells by delivering bioactive cargoes, such as microRNAs (miRNAs). MiRNAs function in multiple steps of HCC development, including metastasis. MiR-374c-5p was previously identified as a tumor suppressor in some malignancies, while the current knowledge of its role in HCC metastasis is still limited. Herein, miR-374c-5p was found to be downregulated in HCC cell lines and clinical samples, and positively related with favorable prognosis in HCC patients.MiR-374c-5p transferred by exosomes derived from bone marrow mesenchymal stem cell (BMSC) suppressed migration, invasion and proliferation of HCC cells.LIMK1 was verified as downstream target gene of miR-374c-5p. Knockdown of LIMK1 reduced invasion, migration and proliferation of HCC cells, whereas overexpression functioned oppositely. The miR-374c-5p/LIMK1 axis suppressed epithelialmesenchymal transition (EMT) by inactivating Wnt/β-catenin pathway. In addition, miR-374c-5p was downregulated and LIMK1 upregulated in TGF-β1 induced EMT.This EMT model could be reversed by LIMK1 silencing or miR-374c-5p overexpression. These results suggest that exo-miR-374c-5p suppresses EMT via targeting LIMK1-Wnt/β-catenin axis and the axis is involved in TGF-β1 induced metastasis of HCC, thereby identifying miR-374c-5p as a potential target for HCC treatment.

Genes Related to Frontonasal Malformations Are Regulated by miR-338-5p, miR-653-5p, and miR-374-5p in O9-1 Cells

“…In addition, miR-653-5p plays a role in cell proliferation in various cancer cells, such as ovarian cancer [ 22 ], papillary thyroid carcinoma [ 23 ], breast cancer [ 24 , 25 , 26 ], gastric cancer [ 27 ], and lung cancer [ 28 , 29 ]. Although miR-374c-5p is less well characterized, recent studies show that miR-374c-5p secreted from mesenchymal stem cells inhibits cancer growth and metastasis formation by regulating the epithelial–mesenchymal transition [ 30 , 31 ].…”

The pivotal role of EMT-related noncoding RNAs regulatory axes in hepatocellular carcinoma

“…Similarly, miR-374c-5p was found to be downregulated in the EMT model and transferred by exosomes derived from bone marrow mesenchymal stem cells (BMSC) suppresses EMT via targeting LIM domain kinase 1 (LIMK1) and inhibiting Wnt/β-catenin and TGF-β1 axes in HCC cells (Ding et al, 2023). Yao et al (2022) identified that lncRNA THEMIS2-211 is upregulated in plasma-derived exosomes from HCC patients.…”

“…In contrast, Huh7 cell-derived exosomes loaded with miR-125b (Exo-125b) blocks EMT and suppresses metastatic potential via inhibiting TGF-β1/SMAD pathways ( Kim et al, 2021 ). Similarly, miR-374c-5p was found to be downregulated in the EMT model and transferred by exosomes derived from bone marrow mesenchymal stem cells (BMSC) suppresses EMT via targeting LIM domain kinase 1 (LIMK1) and inhibiting Wnt/β-catenin and TGF-β1 axes in HCC cells ( Ding et al, 2023 ).…”

Cancer-derived exosomes as novel biomarkers in metastatic gastrointestinal cancer

“…For HCC, exosomal microRNA-27a-3p and miR-374c-5p can respectively upregulate GOLM1 and inactivate Wnt/β-catenin pathway to suppress EMT to inhibit HCC progression [ 159 , 160 ]. Besides, exosomal circ-0072088 can sponge with miR-375 and upregulate MMP-16 to suppress HCC metastasis, and exosomal hsa_circ_0051443 can bound to miR-331-3p to upregulate BAK1 which in turn suppresses HCC progression [ 161 , 162 ].…”