Brn3a/Pou4f1 通过靶向甲状腺癌中的 c-MET/STAT3 信号通路发挥肿瘤抑制作用。
Brn3a/Pou4f1 Functions as a Tumor Suppressor by Targeting c-MET/STAT3 Signaling in Thyroid Cancer.
机构信息
Department of Otolaryngology-Head and Neck Surgery, Chungnam National University College of Medicine, Daejeon, Korea.
Department of Endocrinology and Metabolism, Chungnam National University College of Medicine, Daejeon, Korea.
出版信息
J Clin Endocrinol Metab. 2020 Sep 1;105(9). doi: 10.1210/clinem/dgaa316.
BACKGROUND
Brn3a/Pou4f1 is a class IV POU domain-containing transcription factor and has been found to be expressed in a variety of cancers. However, the mechanism and action of Brn3a in thyroid cancer has not been investigated.
PURPOSE
To investigate the role of Brn3a in thyroid cancer progression and its clinical implication.
METHODS
We examined Brn3a expression status in patients with thyroid cancer and analyzed relationships between Brn3a expression and clinicopathological findings using The Cancer Genome Atlas (TCGA) database. For functional in vitro analysis, proliferation, migration, invasion assay, and Western blotting were performed after overexpression or suppression of Brn3a.
RESULTS
The promoter hypermethylation of Brn3a was found in patients with aggressive thyroid cancer and Brn3a was downregulated in tissues of patients with thyroid cancer. In TCGA database, the low-Brn3a-expression group revealed a more aggressive phenotype, including T stage and extrathyroid extension when compared with the high-Brn3a-expression group. Overexpression of Brn3a suppressed cell migration and invasion via regulation of epithelial-mesenchymal transition (EMT)-associated proteins in thyroid cancer cell lines. Brn3a overexpression also downregulated signal transducer and activator of transcription 3 (STAT3) signaling through suppression of tyrosine-protein kinase Met (c-MET). In contrast, knockdown of Brn3a by small interfering ribonucleic acid (siRNA) significantly increased cell migration and invasion through upregulation of c-MET/STAT3. These results imply that Brn3a suppresses tumor metastasis via c-MET/STAT3 inhibition and EMT suppression in thyroid cancer.
CONCLUSIONS
Our findings show that Brn3a is a potential tumor suppressor that leads to reduced cancer cell migration and invasion in thyroid cancer. Elucidation of the Brn3a-regulated cancer pathways may therefore provide novel therapeutic strategies to control thyroid cancer metastasis.
背景
Brn3a/Pou4f1 是一种 IV 类 POU 结构域转录因子，已在多种癌症中发现表达。然而，Brn3a 在甲状腺癌中的作用机制尚未得到研究。
目的
研究 Brn3a 在甲状腺癌进展中的作用及其临床意义。
方法
我们检测了甲状腺癌患者中 Brn3a 的表达状态，并使用癌症基因组图谱（TCGA）数据库分析了 Brn3a 表达与临床病理特征之间的关系。为了进行体外功能分析，在过表达或抑制 Brn3a 后进行了增殖、迁移和侵袭测定以及 Western blot 分析。
结果
在侵袭性甲状腺癌患者中发现 Brn3a 启动子超甲基化，并且甲状腺癌组织中 Brn3a 下调。在 TCGA 数据库中，与高 Brn3a 表达组相比，低 Brn3a 表达组的 T 分期和甲状腺外侵犯更为明显。在甲状腺癌细胞系中，Brn3a 的过表达通过调节上皮-间充质转化（EMT）相关蛋白抑制细胞迁移和侵袭。Brn3a 的过表达还通过抑制酪氨酸蛋白激酶 Met（c-MET）下调信号转导和转录激活因子 3（STAT3）信号。相比之下，通过小干扰 RNA（siRNA）敲低 Brn3a 通过上调 c-MET/STAT3 显著增加细胞迁移和侵袭。这些结果表明，Brn3a 通过抑制 c-MET/STAT3 抑制和 EMT 抑制抑制甲状腺癌细胞的肿瘤转移。
结论
我们的研究结果表明，Brn3a 是一种潜在的肿瘤抑制因子，可导致甲状腺癌细胞迁移和侵袭减少。阐明 Brn3a 调节的癌症途径可能为控制甲状腺癌转移提供新的治疗策略。
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