LNK不同转录本在甲状腺未分化癌增殖及侵袭转移中的作用及机制

Rapid proliferation, invasion, and metastasis are the main causes of poor prognosis of anaplastic thyroid carcinoma (ATC). We found that the increase of white blood cell and platelet counts in ATC patients was negatively correlated with the prognosis. It is speculated that hematopoietic regulatory genes may be involved in the progression of ATC. LNK is closely related to the occurrence of hematopoietic malignancies, but its relationship with ATC is not clear. We found that two transcripts of LNK gene play different roles in the process of ATC proliferation, invasion and metastasis, LNK1 may enhance the proliferation and anti-apoptotic ability of ATC cells by 1433E/G-Akt-ERK1/2-NFkB-BCLxl axis; LNK2 may enhance the glycolysis of ATC cells through the PRDX1-PI3K-Akt-Glut pathway and increase the level of lactic acid in the cell microenvironment, which induces an increase of invasion and metastasis ability. We intend to use human ATC cell lines and rat models of in situ and lung metastasis with these cell lines to finish the experiments in vitro and in vivo. During the experiments, shRNA or target gene over expression, signal pathway blocking, glucose metabolism intervention measures will be used to explore the specific mechanism of LNK gene in promoting the proliferation and invasion of ATC. The elucidation of this mechanism will provide a new target for the treatment of ATC, and provide a new way to improve the prognosis of patients with ATC.

快速增殖与侵袭转移是甲状腺未分化癌（ATC）预后差的最主要原因，我们发现ATC患者白细胞和血小板计数增高与其预后负相关，推测造血调控基因可能参与ATC的进展。造血抑制基因LNK与造血系统肿瘤发生密切相关，但其与ATC的关系不清楚。我们发现LNK基因两个转录本在ATC增殖和侵袭转移过程中发挥了不同功能，LNK1可能经1433E/G-Akt-ERK1/2-NFkB-BCLxl轴增强ATC细胞增殖与抗凋亡能力；LNK2可能经PRDX1-PI3K-Akt-Glut途径增强ATC细胞糖酵解增加细胞微环境乳酸水平，导致其侵袭转移能力增强。我们拟用人ATC细胞及其建立的原位和肺转移动物模型为研究对象，进行体内外实验，采用目标基因过表达或敲低、信号通路阻断、糖代谢干预等措施，探索LNK基因不同转录本促进ATC增殖和侵袭转移的具体机制，该机制的阐明将为治疗ATC提供新靶点，并为改善ATC患者预后提供新思路。

快速增殖与侵袭转移是甲状腺未分化癌（ATC）预后差的最主要原因，我们既往发现ATC患者白细胞和血小板计数增高与其预后负相关，推测造血调控基因，甚至血小板（PLT）和白细胞本身可能也参与ATC的进展。在前期研究的基础上，我们利用人ATC细胞（ARO、8305C）及其建立的荷瘤鼠动物模型为研究对象，进行体内外实验，采用目标基因过表达或敲低、信号通路靶向阻断、糖代谢调控等措施，发现造血抑制基因LNK不同转录本通过下列具体机制显著增强ATC细胞的增殖与抗凋亡能力、侵袭与转移潜力：LNK1通过1433E/G-Akt-ERK1/2-NFkB-BCLxl轴增强ATC细胞增殖与抗凋亡能力；LNK2经PRDX1-PI3K-Akt-Glut途径增强ATC细胞糖酵解增加细胞微环境乳酸水平，导致其侵袭转移能力增强。进一步我们发现，ATC细胞可以活化血小板（PLT），而活化后的PLT通过分泌趋化因子CCL3，后者与ATC细胞表面的受体CCR5 结合，活化NF-κB 通路，诱导MMP-1上调，导致ATC细胞侵袭和迁移能力显著增强。在本基金的支持下，我们最近还发现在ATC肿瘤微环境，中性粒细胞（NEU）分泌前列腺素E2（PGE2）经PTGER2受体激活wnt/β-catenin通路诱导ATC细胞EMT进而促进其侵袭迁移能力，同时，经激活NFκB通路诱导ATC细胞分泌趋化因子CXCL1，后者正反馈趋化更多NEU向ATC组织浸润，这一正向反馈显著促进了ATC的侵袭迁移能力。上述关于造血因子及PLT、NEU本身在ATC细胞高侵袭转移机制方面的研究结果为治疗ATC提供了新靶点，并为改善ATC患者预后提供新思路。