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Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer

Tian FangInternational Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, ChinaHongwei LvInternational Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, 200438, ChinaGuishuai LvNational Center for Liver Cancer, Shanghai, 201805, ChinaTing LiEastern Hepatobiliary Surgery HospitalChangzheng WangEastern Hepatobiliary Surgery HospitalQin HanEastern Hepatobiliary Surgery HospitalLe‐Xing YuNational Center for Liver Cancer, Shanghai, 201805, ChinaBo SuShanghai Pulmonary HospitalLinna GuoNational Center for Liver Cancer, Shanghai, 201805, ChinaShanna HuangEastern Hepatobiliary Surgery HospitalDan CaoNational Center for Liver Cancer, Shanghai, 201805, ChinaLiang TangEastern Hepatobiliary Surgery HospitalShanhua TangEastern Hepatobiliary Surgery HospitalMengchao WuNational Center for Liver Cancer, Shanghai, 201805, ChinaWen YangNational Center for Liver Cancer, Shanghai, 201805, ChinaHongyang WangNational Center for Liver Cancer, Shanghai, 201805, China. [email protected]

2018en

ABI

Annotatsiya

The communication between tumor-derived elements and stroma in the metastatic niche has a critical role in facilitating cancer metastasis. Yet, the mechanisms tumor cells use to control metastatic niche formation are not fully understood. Here we report that in the lung metastatic niche, high-metastatic hepatocellular carcinoma (HCC) cells exhibit a greater capacity to convert normal fibroblasts to cancer-associated fibroblasts (CAFs) than low-metastatic HCC cells. We show high-metastatic HCC cells secrete exosomal miR-1247-3p that directly targets B4GALT3, leading to activation of β1-integrin-NF-κB signaling in fibroblasts. Activated CAFs further promote cancer progression by secreting pro-inflammatory cytokines, including IL-6 and IL-8. Clinical data show high serum exosomal miR-1247-3p levels correlate with lung metastasis in HCC patients. These results demonstrate intercellular crosstalk between tumor cells and fibroblasts is mediated by tumor-derived exosomes that control lung metastasis of HCC, providing potential targets for prevention and treatment of cancer metastasis.

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Identifikatorlar

DOI: 10.1038/s41467-017-02583-0

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