The incidence rate of thyroid carcinoma ranks ninth among human malignancies, and it accounts for the most frequent malignancy in endocrine-related tumors. This study aimed to investigate the role of long noncoding RNA (lncRNA) ZFAS1 in the metastasis of papillary thyroid carcinoma (PTC) and the potential molecular mechanisms. Both ZFAS1 and MMP3 were highly expressed in thyroid carcinoma and PTC cell, as measured by the q-PCR and TCGA database. In addition, ZFAS1 induced TPC-1 metastasis through inducing the epithelial–mesenchymal transition (EMT) process. Besides, ZFAS1 knockdown by siRNA induced miR-373-3p expression and reduced MMP3 expression, as quantified by q-PCR and Western blotting. According to the luciferase assay, both ZFAS1 and MMP3 were classified as the direct targets of miR-373-3p. However, MMP3 itself did not affect ZFAS1. Using the online prediction tool, CREB3 was predicted as the transcription factor (TF) of ZFAS1 that contained two binding sites on its promoter region, and CREB3 was positively correlated with ZFAS1 in thyroid carcinoma cohorts. Results from the dual-luciferase assay and ChIP-qPCR indicated that both the two binding sites were essential for the transcription of ZFAS1. In conclusion, CREB3 activated lncRNA ZFAS1 at the transcriptional level to promote PTC metastasis by modulating miR-373-3p/MMP3.

中文翻译：

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CREB3 反式激活 lncRNA ZFAS1 通过调节 miR-373-3p/MMP3 调节轴促进甲状腺乳头状癌转移

甲状腺癌的发病率在人类恶性肿瘤中排名第九，是内分泌相关肿瘤中发病率最高的恶性肿瘤。本研究旨在探讨长链非编码RNA（lncRNA）ZFAS1在甲状腺乳头状癌（PTC）转移中的作用及其潜在的分子机制。根据 q-PCR 和 TCGA 数据库测量，ZFAS1 和 MMP3 在甲状腺癌和 PTC 细胞中均高度表达。此外，ZFAS1 通过诱导上皮间质转化 (EMT) 过程诱导 TPC-1 转移。此外，通过 q-PCR 和蛋白质印迹量化，siRNA 敲低 ZFAS1 诱导 miR-373-3 p表达并降低 MMP3 表达。根据荧光素酶测定，ZFAS1 和 MMP3 均被归类为 miR-373-3 p的直接靶标. 但是，MMP3 本身并不影响 ZFAS1。使用在线预测工具，CREB3 被预测为 ZFAS1 的转录因子 (TF)，在其启动子区域包含两个结合位点，并且 CREB3 与甲状腺癌队列中的 ZFAS1 呈正相关。双荧光素酶测定和 ChIP-qPCR 的结果表明，这两个结合位点对于 ZFAS1 的转录都是必不可少的。总之，CREB3 在转录水平激活 lncRNA ZFAS1，通过调节 miR-373-3 p /MMP3促进 PTC 转移。