SMAP1 promotes hepatoblastoma cell proliferation by modulating the C-Kit-activated ERK/MAPK pathway

 Jie Liu, Ke Xu, Hongyue Wang, Yan Cheng, Zihui Cheng, Wenjie Bu, Feifei Wang, Xiaoxuan Zuo, Xiaojian Li, Nan Xia, Qian Dong, Wenli Xiu,  Aiqin Lin

Abstract:

Hepatoblastoma (HB) is the most common pediatric liver malignancy. We investigated the role of SMAP1 in HB proliferation and its mechanism. Sixty-seven HB tissues were analyzed for SMAP1 expression via immunohistochemistry and correlated with clinical outcomes. qRT-PCR quantified SMAP1 mRNA in HB cell lines versus normal hepatocytes. SMAP1 was knocked down (siRNA/lentivirus) or overexpressed (plasmid) in HB cells; proliferation was assessed by CCK-8 and colony formation. A nude-mouse xenograft model was used to evaluate tumorigenicity. Western blotting determined C-Kit and ERK/MAPK pathway activity after SMAP1 modulation. Rescue experiments used ERK activator C16-PAF, inhibitor U0126, or C-Kit inhibitor ISCK03. SMAP1 was upregulated in HB and predicted poor prognosis. Knockdown reduced C-Kit, p-C-Kit, and p-ERK1/2, inhibited proliferation and colony formation, and suppressed xenograft growth. Overexpression produced opposite effects. U0126 reversed ERK1/2 phosphorylation and p-Rb in SMAP1-overexpressing cells, whereas C16-PAF restored ERK signaling and c-Myc/p-Rb in knockdown cells. ISCK03 blocked C-Kit/ERK activation prompted by SMAP1 overexpression. SMAP1 drives HB progression by activating C-Kit-ERK/MAPK signaling, representing a potential therapeutic target.