Sun Yanlei, Sun Bolu, Yang Mei, Deng Qiangqun
Department of Endocrinology, Wuhan Third Hospital, No.216, Guanshan Avenue, Hongshan District, Wuhan, 430000, Hubei, China.
School of the Science and Engineering, Lanzhou University of Technology, Lanzhou, 730050, Gansu, China.
Biochem Genet. 2025 Jul 14. doi: 10.1007/s10528-025-11201-4.
Podocan (PODN) has strong clinical diagnostic significance, and sorafenib is a versatile anti-cancer drug. Yet, neither the individual nor combined effects of PODN and sorafenib on papillary thyroid carcinoma (PTC) malignancy, nor their mechanisms, have been reported. We employed bioinformatics to pinpoint mRNAs significantly downregulated in PTC that negatively affected tumor cell migration. Using qRT-PCR, we quantified PODN and Methyltransferase-like 3 (METTL3) levels in PTC samples. MeRIP, Pearson analysis, and RIP assays validated regulatory links among PODN, METTL3, and IGF2BP1. We treated PTC cells with sorafenib or induced PODN overexpression, then assessed proliferation, migration, and invasion via CCK-8, wound healing, and Transwell assays. Both PODN and METTL3 showed low expression in PTC samples and correlated positively. Sorafenib or high PODN levels suppressed PTC cell survival, migration, and invasion. Elevated PODN also amplified sorafenib's antitumor effects in PTC cells. Moreover, METTL3 increased N6-methyladenosine (mA) methylation of PODN, upregulating PODN mRNA and protein via an IGF2BP1-dependent mechanism. Our findings indicate that PODN inhibits PTC cell invasion, migration, and proliferation, driven by sorafenib-induced upregulation and METTL3-mediated mA methylation. Targeting the sorafenib-METTL3-mA-PODN synergy offers a promising new therapeutic avenue for PTC.
足突蛋白（PODN）具有很强的临床诊断意义，而索拉非尼是一种多用途抗癌药物。然而，PODN和索拉非尼对甲状腺乳头状癌（PTC）恶性肿瘤的单独或联合作用及其机制均未见报道。我们利用生物信息学来确定在PTC中显著下调且对肿瘤细胞迁移有负面影响的mRNA。通过qRT-PCR，我们定量了PTC样本中PODN和甲基转移酶样3（METTL3）的水平。MeRIP、Pearson分析和RIP实验验证了PODN、METTL3和IGF2BP1之间的调控联系。我们用索拉非尼处理PTC细胞或诱导PODN过表达，然后通过CCK-8、伤口愈合和Transwell实验评估细胞的增殖、迁移和侵袭能力。PODN和METTL3在PTC样本中均呈低表达且呈正相关。索拉非尼或高PODN水平可抑制PTC细胞的存活、迁移和侵袭。升高的PODN还增强了索拉非尼对PTC细胞的抗肿瘤作用。此外，METTL3增加了PODN的N6-甲基腺苷（m⁶A）甲基化，通过依赖IGF2BP1的机制上调PODN的mRNA和蛋白水平。我们的研究结果表明，PODN抑制PTC细胞的侵袭、迁移和增殖，这是由索拉非尼诱导的上调和METTL3介导的m⁶A甲基化所驱动的。针对索拉非尼-METTL3-m⁶A-PODN协同作用为PTC提供了一种有前景的新治疗途径。
