Department of tumor cell biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China.
Department of Hepatobiliary, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China.
Cell Death Dis. 2018 May 1;9(5):513. doi: 10.1038/s41419-018-0534-9.
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) frequently 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.
肝癌是全球癌症相关死亡的第二大主要原因。大约 70-90%的原发性肝癌为肝细胞癌（HCC）。目前，由于 HCC 患者转移和/或术后复发率较高，其预后仍不理想。因此，迫切需要新的治疗方法来抑制转移和复发。外泌体是一种小的脂质双层囊泡，与肿瘤的发生和转移有关。Rab27a 是一种小分子 GTPase，通过调节多泡体与质膜的对接来调节外泌体的分泌。然而，Rab27a 是否参与 HCC 细胞来源的外泌体的胞吐作用尚不清楚。上皮间质转化（EMT）常引发转移。HCC 细胞来源的外泌体在 EMT 中的作用尚不清楚。我们发现，高转移性 MHCC97H 细胞来源的外泌体可与低转移性 HCC 细胞相互作用，增加其迁移、趋化和侵袭能力。Rab27a 敲低抑制了 MHCC97H 来源的外泌体的分泌，从而促进了亲本 MHCC97H 细胞的迁移、趋化和侵袭。机制研究表明，用 MHCC97H 来源的外泌体或自我来源的外泌体分泌减少的 MHCC97H 细胞处理的 HCC 细胞的生物学变化是通过 MAPK/ERK 信号通路诱导 EMT 引起的。动物实验表明，阻断外泌体的分泌与增强亲本 MHCC97H 细胞的肺转移和肝内转移有关，而 MHCC97H 细胞中 Rab27a 的异位过表达可挽救体内转移的增强。尾静脉注射 MHCC97H 细胞来源的外泌体可促进体内 HLE 肿瘤的肝内复发。临床上，Rab27a 与血清甲胎蛋白（AFP）水平、血管侵犯和肝硬化呈正相关。本研究阐明了外泌体在 HCC 转移和复发中的作用，提示它们是 HCC 患者有前途的治疗和预后靶点。
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