孤儿核受体NR4A1调控甲状腺未分化癌干细胞特性的重要作用及分子机制

Cancer stem cells (CSCs) have the ability of self-renew and give rise to the heterogeneous tumor cell mass and play a vital role in tumor recurrence. Accumulating evidence suggested that constitutive activation of Wnt/β-catenin and Hedgehog signaling is crucial for cancer stem cell regulation. However, the underlying mechanism is largely unknown. We have previously found that nuclear orphan receptor NR4A1 was down-regulated in anaplastic thyroid cancer (ATC) and inhibited the stemness of ATC cell. Meanwhile, we also found that the negative regulators of Wnt/β-catenin and Hedgehog signaling (Axin2, CXXC4, DKK3, and HHIP) could be transcriptionally regulated by NR4A1. Therefore, we are aiming to systematically explore the mechanism underlying NR4A1-regulated self-renew activity of ATC CSCs via regulation of Wnt/β-catenin and Hedgehog signaling, which would provide novel therapeutic strategies for ATC treatment.

肿瘤干细胞（cancer stem cell, CSCs）是肿瘤中具有自我更新能力并能产生异质性肿瘤细胞的细胞，是放、化疗后残留肿瘤复发的一个重要原因。研究表明Wnt/β-catenin及Hedgehog通路的持续激活在调控肿瘤干细胞中发挥关键作用，但相关分子机制仍不清楚。前期预实验表明孤儿核受体NR4A1在甲状腺未分化癌中表达明显下调。外源性高表达NR4A1抑制甲状腺未分化癌（ATC）的干细胞特性。同时我们也发现NR4A1可以转录调控Wnt/β-catenin及Hedgehog通路的负调控因子Axin2、CXXC4、DKK3及HHIP。以此为基础，本项目将系统性研究NR4A1调控Wnt/β-catenin及Hedgehog通路在ATC肿瘤干细胞中的重要作用，阐明NR4A1调控Wnt/β-catenin及Hedgehog通路的机制，为ATC的治疗提供新的靶点。

甲状腺癌是内分泌系统最常见的恶性肿瘤，其发病率在全世界范围内逐渐升高，进一步深入研究其恶性表型背后的相关分子机制，有利了解其发生发展的过程，并为寻找可能的治疗靶点提供依据。本项目研究发现：1）INAVA通过FGF1调控MMP9的表达，促进甲状腺乳头状癌的恶性进展；2）Trop2通过调控ERK及JNK通路，影响MMP2表达，促进甲状腺癌细胞的侵袭性；3）CITED1通过下调p21及p27的表达，促进甲状腺乳头状癌细胞的增殖；4）DPT通过调控MEK/ERK/MYC通路，抑制甲状腺乳头状癌细胞增殖；5）SOSTDC1通过调控cyclin A2及cyclin E2表达，引起G1/S细胞周期阻滞，抑制甲状腺肿瘤细胞增殖；6）LOC100129940-N参与调控Wnt/β-catenin信号通路，促进甲状腺癌恶性进展。我们的研究表明这些分子可能是参与了甲状腺癌的发生发展。