Membrane-associated ring-CH-type finger (MARCH) proteins belong to the E3 ubiquitin ligase family, which regulates protein stability by increasing ubiquitination. Recent evidence has shown that some MARCH proteins play important roles in cancer development. However, the role of MARCH6 in tumorigenesis, including thyroid tumorigenesis, remains unknown. In this study, we determined that MARCH6 was upregulated in the majority of primary papillary thyroid cancers (PTCs) at both the mRNA and protein levels. Gain-of-function and loss-of-function studies demonstrated that MARCH6 suppressed apoptosis and promoted cell cycle progression, cell proliferation, growth, migration and tumorigenesis in thyroid cancer cells. Mechanistically, MARCH6 interacted with and downregulated DHX9. Knockdown of DHX9 enhanced the proliferative and migratory abilities of thyroid cancer cells. The inhibitory effect of MARCH6 knockdown on thyroid cancer cell growth and migration was also reversed by DHX9 silencing. In addition, MARCH6 activated the AKT/mTOR signaling pathway in a manner dependent on the downregulation of DHX9. Overall, MARCH6 functions as a potential oncogene in thyroid cancer by destabilizing DHX9 and activating AKT/mTOR signaling.

中文翻译：

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MARCH6 通过破坏 DHX9 的稳定性促进甲状腺乳头状癌的发展


膜相关环 CH 型指 (MARCH) 蛋白属于 E3 泛素连接酶家族，通过增加泛素化来调节蛋白质稳定性。最近的证据表明，一些 MARCH 蛋白在癌症发展中发挥着重要作用。然而，MARCH6 在肿瘤发生（包括甲状腺肿瘤发生）中的作用仍不清楚。在这项研究中，我们确定 MARCH6 在大多数原发性甲状腺乳头状癌 (PTC) 中的 mRNA 和蛋白质水平均上调。功能获得和功能丧失研究表明，MARCH6 可抑制甲状腺癌细胞的细胞凋亡并促进细胞周期进程、细胞增殖、生长、迁移和肿瘤发生。从机制上讲，MARCH6 与 DHX9 相互作用并下调 DHX9。 DHX9 的敲除增强了甲状腺癌细胞的增殖和迁移能力。 DHX9 沉默也逆转了 MARCH6 敲低对甲状腺癌细胞生长和迁移的抑制作用。此外，MARCH6 以依赖于 DHX9 下调的方式激活 AKT/mTOR 信号通路。总体而言，MARCH6 通过破坏 DHX9 的稳定性并激活 AKT/mTOR 信号传导，充当甲状腺癌中的潜在癌基因。