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<p>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 (m<sup>6</sup>A) 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 m<sup>6</sup>A methylation. Targeting the sorafenib-METTL3-m<sup>6</sup>A-PODN synergy offers a promising new therapeutic avenue for PTC.</p> Graphical Abstract <p></p>

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m6A Methylation of PODN Regulated by METTL3 Synergizes with Sorafenib to Exhibit Antitumor Function in Papillary Thyroid Cancer

  • 期刊论文

  • 发表日期：

    2025年7月14日

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  • Yanlei Sun,
  • Bolu Sun,
  • Mei Yang,
  • Qiangqun Deng

摘要

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 (m6A) 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 m6A methylation. Targeting the sorafenib-METTL3-m6A-PODN synergy offers a promising new therapeutic avenue for PTC.

Graphical Abstract