HCC-derived exosomes elicit HCC progression and recurrence by epithelialmesenchymal transition through MAPK/ ERK signalling pathway

被引：267

作者：

Chen, Lu ^{[1
,2
]}

Guo, Piao ^{[1
]}

He, Yuchao ^{[1
]}

Chen, Ziye ^{[1
]}

Chen, Liwei ^{[1
]}

Luo, Yi ^{[1
]}

Qi, Lisha ^{[3
]}

Liu, Yuanyuan ^{[4
]}

Wu, Qiang ^{[2
]}

Cui, Yunlong ^{[2
]}

Fang, Feng ^{[2
]}

Zhang, Xiaofang ^{[5
]}

Song, Tianqiang ^{[2
]}

Guo, Hua ^{[1
]}

机构：

[1] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Dept Tumor Cell Biol, Key Lab Canc Prevent & Therapy, Tianjin 300060, Peoples R China

[2] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Dept Hepatobiliary, Key Lab Canc Prevent & Therapy, Tianjin 300060, Peoples R China

[3] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Dept Pathol, Key Lab Canc Prevent & Therapy, Tianjin 300060, Peoples R China

[4] Tianjin Med Univ, Basic Med Coll, Dept Genet, Tianjin 300070, Peoples R China

[5] Tianjin Med Univ, Gen Hosp, Dept Med Lab, Tianjin 300052, Peoples R China

来源：

CELL DEATH & DISEASE | 2018年 / 9卷

基金：

中国国家自然科学基金; 国家高技术研究发展计划(863计划);

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; CANCER; METASTASIS; RAB27A; CELLS; BIOGENESIS; EXPRESSION; PROTEINS;

D O I：

10.1038/s41419-018-0534-9

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Liver cancer is the second most common cause of cancer related death worldwide Approximately 70-90% of primary liver cancers are hepatocellular carcinoma (HCC) Currently, HCC patient prognosis is unsatisfactory due to high metastasis and/or post surgical recurrence rates Therefore, new therapeutic methods for inhibiting metastasis and recurrence are urgently needed Exosomes are small lipid bilayer vesicles that are implicated in tumour development and metastasis Rab27a, a small GTPase, regulates exosome secretion by mediating multivesicular endosome docking at the plasma membrane However, whether Rab27a participates in HCC cell derived exosome exocytosis is unclear Epithelial mesenchymal transition (EMT) freguently initiates metastasis The role of HCC cell derived exosomes in EMT remains unknown We found that exosomes from highly metastatic MHCC97H cells could communicate with low metastatic HCC cells, increasing their migration, chemotaxis and invasion Rab27a knockdown inhibited MHCC97H derived exosome secretion, which consequently promoted migration, chemotaxis and invasion in parental MHCC97H cells Mechanistic studies showed that the biological alterations in HCC cells treated with MHCC97H derived exosomes or MHCC97H cells with reduced self derived exosome secretion were caused by inducing EMT via MAPK/ERK signalling Animal experiments indicated that exosome secretion blockade was associated with enhanced lung and intrahepatic metastasis of parental MHCC97H cells, while ectopic overexpression of Rab27a in MHCC97H cells could rescue this enhancement of metastasis in vivo Injection of MHCC97H cell derived exosomes through the tail vein promoted intrahepatic recurrence of HLE tumours in vivo Clinically, Rab27a was positively associated with serum alpha fetoprotein (AFP) level, vascular invasion and liver cirrhosis Our study elucidated the role of exosomes in HCC metastasis and recurrence, suggesting that they are promising therapeutic and prognostic targets for HCC patients.

引用

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