RETRACTED: Hepatoma Cell-Derived Extracellular Vesicles Promote Liver Cancer Metastasis by Inducing the Differentiation of Bone Marrow Stem Cells Through microRNA-181d-5p and the FAK/Src Pathway

Abstract

Bone marrow mesenchymal stem cells (BMSCs) are beneficial to repair the damaged liver. Tumor-derived extracellular vesicles (EV) are notorious in tumor metastasis. But the mechanism underlying hepatoma cell-derived EVs in BMSCs and liver cancer remains unclear. We hypothesize that hepatoma cell-derived EVs compromise the effects of BMSCs on the metastasis of liver cancer. The differentially expressed microRNAs (miRNAs) were screened. HepG2 cells were transfected with miR-181d-5p mimic or inhibitor, and the EVs were isolated and incubated with BMSCs to evaluate the differentiation of BMSCs into fibroblasts. Hepatoma cells were cultured with BMSCs conditioned medium (CM) treated with HepG2-EVs to assess the malignant behaviors of hepatoma cells. The downstream genes and pathways of miR-181d-5p were analyzed and their involvement in the effect of EVs on BMSC differentiation was verified through functional rescue experiments. The nude mice were transplanted with BMSCs-CM or BMSCs-CM treated with HepG2-EVs, and then tumor growth and metastasis in vivo were assessed. HepG2-EVs promoted fibroblastic differentiation of BMSCs, and elevated levels of α-SMA, vimentin, and collagen in BMSCs. BMSCs-CM treated with HepG2-EVs stimulated the proliferation, migration, invasion and epithelial-mesenchymal-transition (EMT) of hepatoma cells. miR-181d-5p was the most upregulated in HepG2-EVs-treated BMSCs. miR-181d-5p targeted SOCS3 to activate the FAK/Src pathway and SOCS3 overexpression inactivated the FAK/Src pathway. Reduction of miR-181d-5p in HepG2-EVs or SOCS3 overexpression reduced the differentiation of BMSCs into fibroblasts, and compromised the promoting effect of HepG2-EVs-treated BMSCs-CM on hepatoma cells. In vivo, HepG2-EVs-treated BMSCs facilitated liver cancer growth and metastasis. In conclusion, HepG2-EVs promote the differentiation of BMSCs, and promote liver cancer metastasis through the delivery of miR-181d-5p and the SOCS3/FAK/Src pathway.

Cancer-associated fibroblasts promote the stemness and progression of renal cell carcinoma via exosomal miR-181d-5p

“…As miR-181d-5p has been reported to affect metastasis in breast cancer [ 22 ] and liver cancer [ 23 ], we also performed a cell scratch test and transwell assay in RCC cells, and found that upregulating miR-181d-5p expression level obviously increased the cell migration and invasion abilities, while downregulating miR-181d-5p showed the opposite effects (Supplementary Fig. 3A, B ).…”

Cancer-associated fibroblasts promote the stemness and progression of renal cell carcinoma via exosomal miR-181d-5p

“…Several studies reported that miR-181d-5p restrained cell proliferation and metastasis in osteosarcoma and nonsmall-cell lung cancer [37,38]. Whereas, a recent study demonstrated that hepatoma cell derived exosomal miR-181d-5p could facilitate liver cancer metastasis through FAK/Src pathway [39]. Besides, in breast cancer, CAFs exosomal miR-181d-5p facilitated EMT by regulating CDX2/HOXA5 [40].…”

Intercellular crosstalk between cancer cells and cancer-associated fibroblasts via extracellular vesicles

“…EV miR-9-5p suppresses NOX4 expression to inhibit the induction of TGF-β-mediated CAF phenotype in fibroblasts. [ 174 ] miR-21 Hepatocellular carcinoma Generate CAFs from hepatocyte stellate cells through activating PDK1/Akt signalling [ 92 ] miR-1247-3p Hepatocellular carcinoma Generate CAFs expressing inflammatory genes through targeting B4GALT3 to activate β1 integlin/NF-κB signalling [ 49 ] miR-181d-5p Hepatoma cell May induce CAF state via targeting SOCS3 expression in bone-marrow stem cells (BMSCs) [ 93 ] miR-3473b Lewis lung carcinoma Generate inflammatory gene expressing CAFs through activationg NF-κB singnalling [ 94 ] miR-142-3p Lung cancer EVs derived from cancer cells with miR-142-3p over-expression generate CAFs via non-canonical TGF-β signalling [ 96 ] miR-210 Lung cancer Generate CAFs expressing proangiogenic factors through activating JAK2/STAT3 signalling [ 95 ] lncRNA Gm26809 Melanoma Generate CAF properties in NIH3T3 fibroblasts [ 97 ] miR-155 Melanoma Generate CAFs expressing proangiogenic factors through inhibiting SOCS1 to activate JAK2/STAT3 signalling [ 99 ] ...…”