The Effect Of The Interaction Between Liver Cancer Cells And Fibroblasts On Lung Metastasis Of Liver Cancer

Background & Aims:Mestastasis is considered as one of the most important death reasons in primary liver cancer.The intercellular communication in the tumor microenvironment plays a critical role in facilitating tumor metastasis.However,the mechanism with which primary liver cancer cells control lung metastatic niche formation is still obscure.Cancer-associated fibroblasts(CAFs)exhibit more activated traits and promote tumor progression.This study aims to make further understand of the crosstalk between liver caner cells and CAFs in controlling lung metastasis of liver caner.Methods:Lung metastasis models were established by four types of liver cancer cells to compare the different metastatic abilities.Fibroblasts were educated by conditioned media or exosomes from different liver caner cells to compare the different abilities to reprogram fibroblasts to CAFs.The critical exosomal miRNA and signaling pathway in fibroblasts reprogramming were identified to make further understand of the communication between liver caner cells and CAFs.The critical miRNA expression was detected in clinical hepatocellular carcinoma tissues and serums to determine the correlation with lung metastasis of liver cancer.Results:High metastatic liver caner cells exhibit higher ability to active normal fibroblasts to CAFs,than low metastatic liver caner cells.Exosomal miR-1247-3p,characteristically secreted by high metastatic liver caner cells,is a potent regulator of CAFs activation and lung metastasis of liver cancer.Mechanistically,in fibroblasts,tumor-derived exosomal miR-1247-3p directly targets B4GALT3 and activate ?1-integrin-NF-?B signaling pathway.Activated CAFs exhibit higher capacity in secretion of pro-inflammatory cytokines(IL-6and IL-8),and further promote stemness,EMT and tumor growth in liver cancer.Clinical data suggest that high serum exosomal miR-1247-3p expression is correlated with lung metastasis of liver cancer.Conclusions:This study indicate that in lung metastatic niche,high metastasis liver cancer cells release exosomal miR-1247-3p to activate ?1-integrin-NF-?B signaling by targeting B4GALT3 in fibroblasts,and thus reprograms fibroblasts into CAFs.Activated CAFs promote tumor progression by enhanced secretion of pro-inflammatory cytokines.This crosstalk between tumor cells and fibroblasts promotes lung metastasis of liver cancer and may contribute to new therapeutic strategies of cancer metastasis.