Transcription Factor HOXA9 is Linked to the Calcification and Invasion of Papillary Thyroid Carcinoma
Transcription Factor HOXA9 is Linked to the Calcification and Invasion of Papillary Thyroid Carcinoma
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DOI：
10.1038/s41598-019-43207-5
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发表时间：
2019-05-01
影响因子：
4.6
通讯作者：
Choi, Yong Jun
中科院分区：
文献类型：
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作者：
Jin, Yilan;Kim, Hyeung Kyoo;Choi, Yong Jun
钙化是诊断甲状腺乳头状癌的重要指标。runt相关转录因子2 （RUNX2）是一种与成骨分化相关的主要转录因子，据报道与PTC钙化和侵袭性有关。然而，它在这一过程中的调节作用有些不明确。在这里，我们试图鉴定调控RUNX2的基因，并阐明其在PTC癌变和钙化中的功能。实时荧光定量PCR检测runx2上游基因在Nthy-Ori 3-1正常甲状腺细胞和TPC1、BHP10-3 PTC细胞系中的表达情况。克隆RUNX2启动子后，对候选基因进行荧光素酶和染色质免疫沉淀试验。我们发现RUNX2启动子活性被同源盒家族A9 （HOXA9）增强。研究发现，过表达HOXA9可增强碱性磷酸酶活性、矿化和体外肿瘤细胞的迁移和侵袭，而下调则具有相反的作用。这些结果表明，作为RUNX2的正调控因子，HOXA9可以促进PTC的钙化、迁移和侵袭。我们的数据提高了对PTC微钙化的分子机制以及肿瘤发生的理解。
Calcification is important for the diagnosis of papillary thyroid carcinoma (PTC). Runt-related transcription factor 2 (RUNX2), a master transcription factor associated with osteogenic differentiation, is reportedly related to PTC calcification and invasiveness. However, its regulatory role in this process is somewhat uncharacterized. Here, we attempted to identify genes that regulate RUNX2 and clarify its function in PTC carcinogenesis and calcification. The expression of RUNX2-upstream genes was evaluated by real-time PCR in Nthy-Ori 3-1 normal thyroid cells and TPC1 and BHP10-3 PTC cell lines. Luciferase and chromatin immunoprecipitation assays were performed with candidate genes after cloning the RUNX2 promoter. We found that RUNX2 promoter activity was enhanced by homeobox family A9 (HOXA9). Over-expression of HOXA9 was found to enhance alkaline phosphatase activity, mineralization, and in vitro tumour cell migration and invasion, whereas downregulation had the opposite effects. These results indicate that HOXA9, a positive regulator of RUNX2, can enhance calcification, migration, and invasion in PTC. Our data improve the understanding of the molecular mechanisms of microcalcification in PTC as well as tumorigenesis.