Endocytosis is an essential component of cell motility, which facilitates the malignant behavior of cancer. Sorting nexin (SNX) family members are associated with tumor progression. However, the role and mechanism of SNX5 in hepatocellular carcinoma (HCC) progression remain largely unknown. In this study, we investigated the clinical significance and possible involvement of SNX5 in the progression of HCC. Here, we showed that SNX5 was upregulated in tumors compared with adjacent nontumorous tissues in HCC patients. The upregulation of SNX5 in HCC was associated with vascular invasion, intrahepatic metastasis, and poor prognosis. The overexpression of SNX5 promoted HCC cell proliferation, migration, invasion, and metastasis, whereas silencing SNX5 expression resulted in decreased cell proliferation, migration, and invasion. Knockdown of SNX5 significantly inhibited HCC cell proliferation by inducing G1/S transition arrest. Mechanistically, we demonstrated that SNX5 promoted cell proliferation, migration, and invasion via the activation of the EGFR-ERK1/2 pathway by blocking EGF-mediated EGFR internalization. We found that SNX5 interacted with EGFR in HCC cells. Moreover, SNX5-induced cell proliferation, migration, and invasion were partially reversed by the knockdown of EGFR or by ERK1/2 inhibitors. In addition, we demonstrated that SNX5 knockdown sensitized HCC cells to tyrosine kinase inhibitors, including erlotinib and sorafenib. Taken together, our results indicate that SNX5 promotes HCC cell proliferation and metastasis via inhibiting the endocytosis and degradation of EGFR, thereby activating the ERK1/2 signaling pathway. Our work also suggests that SNX5 is a potential therapeutic target for HCC.

内吞作用是细胞运动的重要组成部分，它促进了癌症的恶性行为。排序连接蛋白 (SNX) 家族成员与肿瘤进展有关。然而，SNX5 在肝细胞癌 (HCC) 进展中的作用和机制仍然很大程度上未知。在这项研究中，我们调查了 SNX5 在 HCC 进展中的临床意义和可能参与。在这里，我们发现与 HCC 患者的邻近非肿瘤组织相比，SNX5 在肿瘤中上调。HCC中SNX5的上调与血管侵犯、肝内转移和预后不良有关。SNX5的过表达促进HCC细胞增殖、迁移、侵袭和转移，而沉默SNX5表达导致细胞增殖、迁移和侵袭减少。SNX5 的敲低通过诱导 G1/S 过渡期阻滞显着抑制 HCC 细胞增殖。从机制上讲，我们证明 SNX5 通过阻断 EGF 介导的 EGFR 内化来激活 EGFR-ERK1/2 通路来促进细胞增殖、迁移和侵袭。我们发现 SNX5 与 HCC 细胞中的 EGFR 相互作用。此外，SNX5 诱导的细胞增殖、迁移和侵袭被 EGFR 的敲低或 ERK1/2 抑制剂部分逆转。此外，我们证明了 SNX5 敲低使 HCC 细胞对酪氨酸激酶抑制剂敏感，包括厄洛替尼和索拉非尼。总之，我们的研究结果表明，SNX5 通过抑制 EGFR 的内吞和降解来促进 HCC 细胞增殖和转移，从而激活 ERK1/2 信号通路。