Hepatoma cell‐secreted exosomal microRNA‐103 increases vascular permeability and promotes metastasis by targeting junction proteins

Hepatology - Tập 68 Số 4 - Trang 1459-1475 - 2018
Jian‐Hong Fang1, Jun Zhang1, Li‐Ru Shang1, Yuwei Luo1, Yi‐Fang Lin1, Yunfei Yuan2, Shi‐Mei Zhuang1,3
1Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine,Sun Yat‐sen University,Guangzhou,China
2Department of Hepatobilliary Oncology, Cancer Center,Sun Yat‐sen University,Guangzhou,China
3Key Laboratory of Liver Disease of Guangdong Province, The Third Affiliated Hospital,Sun Yat‐sen University,Guangzhou,China

Tóm tắt

Increased vascular permeability facilitates metastasis. Emerging evidence indicates that secreted microRNAs (miRNAs) may mediate the crosstalk between cancer and stromal cells. To date, whether and how secreted miRNAs affect vascular permeability remains unclear. Based on deep sequencing and quantitative PCR, we found that higher level of serum miR‐103 was associated with higher metastasis potential of hepatocellular carcinoma (HCC). The in vitro endothelial permeability and transendothelial invasion assays revealed that the conditioned media or exosomes derived from high miR‐103‐expressing hepatoma cells increased the permeability of endothelial monolayers, but this effect was attenuated if exosome secretion of hepatoma cells was blocked by silencing ALIX and HRS or if miR‐103 within hepatoma or endothelial cells was antagonized. Most importantly, pretreating endothelial monolayers with exosomes that were from stable miR‐103‐expressing hepatoma cells facilitated the transendothelial invasion of tumor cells, and this role of exosomes was abrogated by inhibiting miR‐103 in endothelial cells. Further in vivo analyses disclosed that mice with xenografts of stable miR‐103‐expressing hepatoma cells exhibited higher vascular permeability in tumor, higher level of exosomal miR‐103 and greater number of tumor cells in blood circulation, and increased rates of hepatic and pulmonary metastases, compared to control mice. Mechanism investigations revealed that hepatoma cell‐secreted miR‐103 could be delivered into endothelial cells via exosomes, and then attenuated the endothelial junction integrity by directly inhibiting the expression of VE‐Cadherin (VE‐Cad), p120‐catenin (p120) and zonula occludens 1. Moreover, miR‐103 could also promote tumor cell migration by repressing p120 expression in hepatoma cells. Conclusion: Hepatoma cell‐secreted exosomal miR‐103 increases vascular permeability and promotes tumor metastasis by targeting multiple endothelial junction proteins, which highlights secreted miR‐103 as a potential therapeutic target and a predictive marker for HCC metastasis. (Hepatology 2018).

Từ khóa


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Hepatology

Tập 68 Số 4

1459-1475

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