先前的研究表明，血小板通过与循环肿瘤细胞（CTC）结合来促进肿瘤转移。然而，血小板在原发肿瘤部位癌细胞的上皮-间质转化（EMT）中的作用，即肿瘤转移的关键初始步骤，仍有待阐明。在这里，我们发现血小板释放通过 AMPK/mTOR 诱导的自噬增强肝细胞癌细胞 (HCC) 的 EMT 和运动性。 RNA-seq表明血小板释放物改变了癌细胞的TGF-β信号通路。抑制 TGFBR 或删除血小板 TGF-β1 可抑制血小板释放诱导的 AMPK/mTOR 通路激活和自噬。与Pf4cre-相比； Tgfb1fl/fl小鼠，在Pf4cre上建立的HCC原位模型； Tgfb1fl/fl小鼠原发肿瘤中TGF-β1水平降低，这与癌细胞EMT、自噬、迁移能力和肿瘤转移能力降低相对应。通过敲除癌细胞中的 Atg5 来抑制自噬，可以消除血小板释放的 TGF-β1 诱导的 EMT 和转移。临床上，较高的血小板计数与 HCC 患者原发肿瘤中 TGF-β1、LC3 和 N-cad 表达增加相关，表明血小板与 HCC 进展之间存在联系。我们的研究表明，血小板通过 AMPK/mTOR 途径诱导 HCC 细胞自噬，从而促进原发肿瘤和 HCC 转移中的癌细胞 EMT。这些发现为血小板在 HCC 转移中的作用以及 HCC 转移的潜在治疗靶点提供了新的见解。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Previous research has revealed that platelets promote tumor metastasis by binding to circulating tumor cells (CTCs). However, the role of platelets in epithelial-mesenchymal transition (EMT) of cancer cells at the primary tumor site, the crucial initial step of tumor metastasis, remains to be elucidated. Here, we found that platelet releasate enhanced EMT and motility of hepatocellular carcinoma (HCC) cells via AMPK/mTOR-induced autophagy. RNA-seq indicated that platelet releasate altered TGF-β signaling pathway of cancer cells. Inhibiting TGFBR or deleting platelet TGF-β1 suppressed AMPK/mTOR pathway activation and autophagy induced by platelet releasate. Compared with Pf4cre-; Tgfb1fl/fl mice, HCC orthotopic models established on Pf4cre+; Tgfb1fl/fl mice showed reduced TGF-β1 in primary tumors, which corresponded with decreased cancer cell EMT, autophagy, migration ability and tumor metastasis. Inhibition of autophagy via Atg5 knockdown in cancer cells negated EMT and metastasis induced by platelet-released TGF-β1. Clinically, higher platelet count correlated with increased TGF-β1, LC3 and N-cad expression in primary tumors of HCC patients, suggesting a link between platelets and HCC progression. Our study indicates that platelets promote cancer cell EMT in the primary tumor and HCC metastasis through TGF-β1-induced HCC cell autophagy via the AMPK/mTOR pathway. These findings offer novel insights into the role of platelets in HCC metastasis and the potential therapeutic targets for HCC metastasis.Copyright © 2024 Elsevier B.V. All rights reserved.