SNX17 mediates STAT3 activation to promote hepatocellular carcinoma progression via a retromer dependent mechanism.

Endocytosis has emerged as a key regulator of malignant behavior in cancer. Members of the sorting nexin (SNX) family have been found to be dysregulated in various cancers and play significant roles in regulating tumor metastasis. However, the role and mechanism of SNX17 in hepatocellular carcinoma (HCC) progression remain largely unknown. Here, we found that upregulation of SNX17 in HCC was associated with poor prognosis. Overexpression of SNX17 promoted HCC cell proliferation, migration, invasion, and metastasis, whereas silencing SNX17 expression resulted in opposite effects. Knockdown of SNX17 induced G1/S phase arrest and apoptosis. We discovered that SNX17 directly interacted with STAT3 and increased its phosphorylation in a retromer-dependent manner. SNX17-retromer complex acted as a platform for IL-6-induced STAT3 activation. Activated STAT3 then increased c-Myc expression and promoted mitochondrial oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis. SNX17 overexpression-induced OXPHOS was reversed by c-Myc inhibitor. Knockdown of STAT3 expression or treatment with a STAT3 inhibitor significantly attenuated SNX17-enhanced proliferation and invasion. Taken together, our results indicate that SNX17 promotes HCC cell proliferation and metastasis through direct interaction with STAT3 in a retromer-dependent manner, thereby activating the STAT3/c-Myc signaling pathway and enhancing OXPHOS. These findings suggest that SNX17 is a potential therapeutic target for HCC.