Lnc-HERC2-1对甲状腺癌增殖、侵袭和转移的调控作用及其机制研究

It is known that LncRNA are associated with the occurrence, progression and recurrence of tumor and Fibronectin (FN) can promote tumor proliferation, invasion and metastasis. Our preliminary data showed that the expression of Lnc-HERC2-1 is negatively correlated with FN, and FN can be negatively regulated byLnc-HERC2-1. Thus we infer that Lnc-HERC2-1 involved in the regulation of proliferation, invasion and metastasis of thyroid carcinoma through regulating the expression of FN. In the present study by detecting the expressions of Lnc-HERC2-1 and FN in thyroid carcinoma tissues and adjacent tissues to confirm that Lnc-HERC2-1 and FN are related to thyroid carcinoma. Then, we’ll use the gene silencing technique to clarify whether Lnc-HERC2-1 participates in the proliferation, invasion and metastasis of thyroid carcinoma by regulating the FN expression through TGF-β signal pathway. Finally, we’ll verify the role of Lnc-HERC2-1 in thyroid carcinoma in vivo. We aim to characterize the modulating action and possible mechanisms of Lnc-HERC2-1 on the proliferation, invasion and metastasis of thyroid carcinoma, which will provide a novel basis and strategy for thyroid carcinoma therapy.

研究证明LncRNA与肿瘤的发生、进展和复发相关，FN具有促肿瘤增殖、侵袭和转移的作用。前期研究显示：Lnc-HERC2-1在甲状腺癌中表达下调，而FN上调，且Lnc-HERC2-1能够转录负调节FN的表达。由此，我们推测，Lnc-HERC2-1通过调节FN的表达参与甲状腺癌增殖、侵袭和转移的调控。在本研究中，我们首先检测甲状腺癌组织中Lnc-HERC2-1和FN的表达，确定二者与甲状腺癌相关。再利用基因沉默等技术阐明Lnc-HERC2-1通过TGF-β通路负向调控FN转录，影响甲状腺癌的增殖、侵袭和转移。最后体内验证Lnc-HERC2-1在甲状腺癌中的作用。本研究最终目的是明确Lnc-HERC2-1对甲状腺癌增殖、侵袭和转移的调控作用及其可能机制，为治疗甲状腺癌提供新的思路和依据。

甲状腺癌是来源于甲状腺滤泡上皮细胞的一种常见的头颈部恶性内分泌系统肿瘤，甲状腺乳头状癌(Papillary Thyroid Carcinoma，PTC)占甲状腺癌的80-85%。从2000年到2018年，甲状腺癌发病率几乎增加了8倍，甲状腺癌的研究也越来越受到科研工作者重视。基因芯片结果显示FN1、COL4A-1、TPO等364个基因在甲状腺乳头状癌中差异表达，n407932、n336302、LncHERC2-1等228个差异表达的LncRNA，GO分析提示TGF-β信号通路、ECM-受体相互作用、甲状腺激素合成等通路存在显著富集。LncHERC2-1在甲状腺乳头状癌组织中低表达，FN在甲状腺乳头状癌组织中高表达，二者表达水平负相关。Lnc-HERC2-1通过负向调控FN表达影响甲状腺乳头状癌细胞TPC-1的增殖、侵袭和转移。COL4A-1在甲状腺组织中高表达，miR-152在甲状腺乳头状癌中低表达，COL4A-1是miR-152的靶基因。miR-152靶向COL4A-1调控甲状腺乳头状癌的上皮间充质转化。甲状腺乳头状癌血清样本经代谢组学分析后共筛选出组胺、精胺、3-甲氧基肾上腺素、亚精胺、β-丙氨酸、α-亚油酸乙醇酰胺、油酰单乙醇胺、、反式-2-十四烯基肉碱、3-羟基己二烯基肉碱、D-α-氨基丁酸、5-羟色胺、二十二碳五烯酸、磷酸胆碱、花生四烯酸乙醇胺等22个差异性代谢物（FC＞1.2，p值＜0.05）。OPLS-DA分析提示甲状腺乳头状癌与甲状腺结节患者的代谢轮廓表现出显著差异，通路分析显示β-丙氨酸代谢、谷胱甘肽代谢/精氨酸和脯氨酸代谢通路存在差异。ROC分析提示组胺、精胺、3-甲氧基肾上腺素、β-丙氨酸、α-亚油酸乙醇酰胺、亚精胺、N-花生酰甘氨酸可作为甲状腺乳头状癌与甲状腺结节鉴别诊断的生物标志物。