Papillary thyroid cancer (PTC) is one of the most prevalent endocrine malignancies. Herein, we aimed to provide a new viewpoint for the PTC progression and explore a new target for the effective therapy for PTC. We found that E26 transformation specific (ETS) variant 4 (ETV4, an ETS family transcription factor) was upregulated in PTC tissues and cells. In vitro experiments exhibited that silencing ETV4 suppressed PTC cell proliferation and cell cycle progression, while the overexpression of ETV4 gained the opposite results. Dual-luciferase reporter assay highlighted that ETV4 could upregulate the solute carrier family 7 member 11 (SLC7A11, a key role for cysteine uptake in ferroptosis) transcription by binding to its promoter region directly. Moreover, the viability inhibition of PTC cells induced by the knockdown of ETV4 was at least partly through the promotion of ferroptosis upon the downregulation of SLC7A11. In in vivo experiment, the results showed that the downregulation of ETV4 repressed the tumor development through the low expression of SLC7A11, and the ETV4 overexpression obtained the contrary effects. Overall, the data suggested that the knockdown of ETV4 suppressed the PTC progression by promoting ferroptosis upon SLC7A11 downregulation.

中文翻译：

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敲除 ETV4 通过在 SLC7A11 下调后促进铁死亡来抑制甲状腺乳头状癌的发展

甲状腺乳头状癌（PTC）是最常见的内分泌恶性肿瘤之一。在此，我们旨在为PTC的进展提供一个新的视角，并为PTC的有效治疗探索一个新的靶点。我们发现 E26 转化特异性 (ETS) 变体 4（ETV4，ETS 家族转录因子）在 PTC 组织和细胞中上调。体外实验表明，沉默ETV4 会抑制 PTC 细胞增殖和细胞周期进程，而ETV4的过表达则获得相反的结果。双荧光素酶报告基因检测强调ETV4可以上调溶质载体家族 7 成员 11 ( SLC7A11，半胱氨酸摄取在铁死亡中的关键作用）转录通过直接结合其启动子区域。此外，由ETV4敲低诱导的 PTC 细胞活力抑制至少部分是通过 SLC7A11 下调促进铁死亡。在体内实验中，结果表明，下调ETV4通过的低表达抑制肿瘤发展SLC7A11，并且ETV4过度表达所获得的相反效果。总体而言，数据表明ETV4的敲低通过在SLC7A11下调时促进铁死亡来抑制 PTC 进展。