醛酮还原酶AKR1C3通过调控PPARγ促进甲状腺癌靶向BRAF耐药的机制研究

难治性甲状腺癌因缺乏有效治疗手段而成为甲状腺癌的主要死因，靶向BRAF治疗是最有前景的治疗手段之一，但耐药现象限制了其应用。醛酮还原酶AKR1C3能调节激素水平从而激活相应的核受体参与肿瘤增殖、转移和耐药过程。课题组前期通过RNA测序筛选并验证AKR1C3在甲状腺癌靶向BRAF耐药细胞株中显著上调；敲低其表达可上调PPARγ并抑制EGFR/Akt信号通路，以及增敏靶向BRAF疗效。由此推测：AKR1C3通过抑制PPARγ进而激活EGFR/Akt信号通路引起靶向BRAF耐药，抑制AKR1C3或激活PPARγ是提高靶向BRAF治疗敏感性的潜在治疗手段。本课题旨在明确AKR1C3对甲状腺癌靶向BRAF治疗敏感性的影响；进一步研究AKR1C3调控靶向治疗耐药的分子机制；最后在动物模型中探索基于该调控通路的联合方案，为难治性甲状腺癌患者的治疗提供新思路。

Refractory thyroid cancer has become the main cause of death for patients with thyroid cancer due to the lack of effective treatment. Targeted BRAF therapy is one of the most promising treatments, but drug resistance is common. Aldosterone reductase family 1, member C3 (AKR1C3) promotes tumor proliferation, metastasis and drug resistance by regulating hormone levels and activating corresponding nuclear receptors. By RNA sequencing analysis, we initially identified AKR1C3 to be significantly up-regulated in vemurafenib-resistant thyroid cancer cells; knockdown of its expression could activate PPARγ and inhibit EGFR/Akt signaling pathway, thus augmented the antitumor effects of BRAF inhibition. Therefore, we hypothesized that AKR1C3 was related with BRAF inhibition resistance by inhibiting PPARγ and activating EGFR/Akt signaling pathway. Inhibiting AKR1C3 expression or activating PPARγ could be beneficial to overcome drug resistance. Here we design this study to investigate the role of AKR1C3 during BRAF inhibition of thyroid cancer, and further explore the underlying molecular pathway involved in AKR1C3 regulation and drug resistance. Finally, by in vivo/vitro experiments, we verify the combined therapy via regulating AKR1C3 and PPARγ. This study will ultimately provide novel clinical treatment for patients with refractory thyroid cancer.