PAX3 is a novel tumor suppressor by regulating the activities of major signaling pathways and transcription factor FOXO3a in thyroid cancer.
PAX3 is a novel tumor suppressor by regulating the activities of major signaling pathways and transcription factor FOXO3a in thyroid cancer.
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PAX3是一种新型肿瘤抑制因子，通过调节甲状腺癌中主要信号通路和转录因子FOXO3a的活性
DOI：
10.18632/oncotarget.10753
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发表时间：
2016-08-23
期刊：
影响因子：
--
通讯作者：
Hou P
中科院分区：
文献类型：
--
作者：
Liu W;Sui F;Liu J;Wang M;Tian S;Ji M;Shi B;Hou P
配对盒3（PAX 3）在胚胎发育早期在神经系统和一些中胚层衍生结构中的空间限制域中表达。近年来，发现它在不同类型的癌症组织和细胞系中过表达，包括胶质母细胞瘤、神经母细胞瘤、黑色素瘤、横纹肌肉瘤、尤文肉瘤和胃癌，这表明它可能在这些癌症中作为癌基因发挥作用。然而，它在甲状腺癌中的作用仍然完全不清楚。本研究旨在探讨PAX 3在甲状腺肿瘤发生中的作用及相关分子机制。使用定量RT-PCR（qRT-PCR）和甲基化特异性PCR（MSP）检测，我们证明PAX 3在原发性甲状腺癌组织和甲状腺癌细胞系中经常被启动子甲基化下调。此外，我们的数据表明，PAX 3的异位表达显着抑制甲状腺癌细胞的增殖，集落形成，迁移和侵袭，诱导细胞周期阻滞和凋亡，并延迟裸鼠的致瘤潜力。PAX 3通过抑制磷脂酰肌醇-3-激酶（PI 3 K）/Akt和MAPK/Erk等信号通路的活性，增强转录因子FOXO 3a的表达和活性，发挥其抑癌作用。总之，我们的研究结果提供了深入了解PAX 3作为一种新的功能性肿瘤抑制因子在甲状腺癌中的作用，通过调节PI 3 K/Akt和MAPK信号通路和转录因子FOXO 3a的活性，并证明表观遗传学改变，如启动子甲基化应该是PAX 3失活的主要机制。
Paired box 3 (PAX3) is expressed early during embryonic development in spatially restricted domains in the nervous system and in some mesodermally-derived structure. In recent years, it is found to be overexpressed in different types of cancer tissues and cell lines including glioblastomas, neuroblastomas, melanomas, rhabdomyosarcomas, Ewing sarcomas and gastric cancers, suggesting that it may function as an oncogene in these cancers. However, its role in thyroid cancer remains totally unclear. The aim of this study was to explore the functions and related molecular mechanism of PAX3 in thyroid tumorigenesis. Using quantitative RT-PCR (qRT-PCR) and Methylation-specific PCR (MSP) assays, we demonstrated that PAX3 was frequently down-regulated by promoter methylation in both primary thyroid cancer tissues and thyroid cancer cell lines. In addition, our data showed that ectopic expression of PAX3 dramatically inhibited thyroid cancer cell proliferation, colony formation, migration and invasion, induced cell cycle arrest and apoptosis and retarded tumorigenic potential in nude mice. Mechanically, PAX3 exerted its tumor suppressor function by inhibiting the activity of major signaling pathways including the phosphatidylinositol-3-kinase (PI3K)/Akt and MAPK/Erk pathways, and enhancing expression and activity of transcription factor FOXO3a. Altogether, our findings provided insight into the role of PAX3 as a novel functional tumor suppressor in thyroid cancer through modulating the activities of PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a, and demonstrated that epigenetic alterations such as promoter methylation should be a major mechanism of PAX3 inactivation in this cancer.