miR-106a对乳头状甲状腺癌碘-131摄取功能的影响及其机制

Non-131I-avid and "dedifferentiation" phenomenon are the two major obstacles to iodine-131 treatment of papillary thyroid carcinoma (PTC) with lung metastases. In our preliminary work, the serum miRNA detection and biological analysis have been carried out between the two groups of PTC patients with and without 131I-avid lung metastases. MiR-106a was found to be significantly up-regulated in non-131I-avid lung metastases of PTC patients and might regulate the MAPK signal pathway by several genes, such as MAPK1，which would down-regulate the ability of 131I uptake for PTC cells. To verify the effect and mechansim of miR-106a on the iodine-131 of papillary thyroid cancinoma , we will transent miR-106a and miR-106a into PTC-K1 cell and up-regulate and down-regulate miR-106a,observing the changes of 131I-avid function of PTC-K1 cell ,MAPK signal pathway related-genes and proteins and iodide-handling related-genes and proteins to make clear whether miR-106a would regulate the ability of 131I uptake of PTC-K1 cell. From the new perspective of serum miRNA, this study may lay the foundation for revealing the mechanism of 131I uptake in lung metastases of PTC and provide new ideas for 131I therapy of PTC with lung metastases.

转移灶不摄取碘-131( 131I )和"失分化"现象是131I治疗乳头状甲状腺癌（PTC）肺转移的主要障碍。我们前期工作发现miR-106a在不摄取131I肺转移患者血清中明显上调，并可能通过MAPK1等基因激活MAPK信号通路,使NIS和TSHR表达下调，导致131I摄取功能下降。为了揭示miR-106a对PTC 131I摄取功能的影响及机制，本研究拟分别将miR-106a和反义-miR-106a转染到具有摄取131I功能的PTC-K1细胞中,通过上调和下调miR-106a的表达，利用Western-blot、qRT-PCR 检测NIS和TSHR基因及蛋白、MAPK信号通路相关基因及蛋白表达水平的变化，并利用摄取实验检测131I摄取功能的变化；以阐明miR-106a对PTC-K1细胞摄取131I功能的影响及机制，为不摄取131I的PTC肺转移治疗提供新的思路和靶点。

放射性核素碘-131是治疗乳头状甲状腺癌肺转移灶的首选方法，然而临床上约30％的DTC肺转移患者在进行治疗过程或其自然发展过程中病灶摄碘能力降低或丧失，导致碘-131治疗效果下降或无效。越来越多的研究证实：miRNA与肿瘤的发生、发展、转移、预后及耐药性密切相关。本研究通过基因芯片筛选技术发现miR-106a在乳头状甲状腺肺转移患者中明显上调，并通过生物信息分析预测miR-106a可能通过MAPK通路调节乳头状甲状腺癌碘-131摄取功能。双荧光素酶和体外细胞实验证实：miR-106a可靶向调节RABA基因3’-UTR，使其表达下调；导致MAPK信号通路激活, 从而引起NIS、TSHR表达下调和甲状腺癌细胞碘-131摄取功能降低。实验亦证实: RABA基因下调,可同时激活MEKK2-ERK1/2 和 MEKK2-ERK5,促进甲状腺癌细胞的分化和使其侵袭性增高；同时激ASK1-p38通路，抑制甲状腺癌细胞的凋亡。本研究通过揭示相关分子生物学机制，为不摄取碘-131肺转移患者获得新的治疗靶点奠定了理论基础。