驱动甲状腺癌细胞侵袭转移的新机制：C1orf106激活的信号传导

The initial stage of metastatic progression is the biological event referred to as epithelial-mesenchymal transition (EMT) and distant metastasis of cancer are responsible for most cancer-related deaths. It has been well demonstrated that constitutive activation of NF-κB signaling plays an important role in regulation of EMT and metastasis of cancer cells. Our preliminary studies showed that: 1) C1orf106 could induce EMT and promote the invasion of thyroid cancer cells; 2) C1orf106 could bind to NF-κB p65 and thereby enhancing its nucleus translocation; 3) miRNA array showed that miR-130a was significantly upregulated by C1orf106; 4) the negative regulators of NF-κB signaling (Rnf11, Kdm2a, and Cyld) could be regulated by miR-130a. Based on these, our aim in current proposal is to systematically investigate the mechanism underlying C1orf106-induced EMT and invasion via activation of NF-κB signaling in thyroid cancer, which may put new insights into the therapeutic strategies for thyroid cancer.

上皮细胞间质化（EMT）是肿瘤发生转移的早期关键事件，而发生远处转移是导致肿瘤患者死亡的主要原因之一。研究表明NF-κB信号通路的持续激活在肿瘤细胞发生EMT及侵袭转移中起重要作用，但相关分子机制仍不明确。前期预实验我们发现C1orf106可以使甲状腺癌细胞发生EMT并促进细胞的侵袭能力。我们还发现C1orf106可以结合NF-κB p65并促进其核转位。miRNA芯片显示miR-130a受C1orf106上调明显，而miR-130a可以通过抑制NF-κB通路的负性调节因子Rnf11、Kdm2a及Cyld而激活NF-κB通路。以这些为基础，本项目将系统性的研究C1orf106调控NF-κB信号通路在诱导肿瘤细胞EMT及侵袭转移中的重要作用，深入阐述C1orf106持续激活NF-κB通路的机理，为甲状腺癌的治疗寻找新靶点。

本项目发现C1orf106（INAVA）在甲状腺乳头状癌（PTC）中表达明显升高并与患者的淋巴结转移相关。体内细胞及体外动物实验表明C1orf106促进PTC细胞侵袭转移。机制研究发现C1orf106通过FGF1调控MMP9的表达，从而促进PTC恶性进展。同时我们还探讨了Trop2、LOC100129940-N、CITED1、DPT及SOSTDC1等在甲状腺癌中的相关生物学意义及分子机制。这些研究发现：1）Trop2通过活化ERK及JNK通路促进MMP2表达从而促进甲状腺肿瘤侵袭性；2）LOC100129940-N通过调控Wnt/β-catenin信号通路促进甲状腺癌恶性进展；3) CITED1通过调控 p21和 p27的表达促进PTC细胞增殖；4）DPT通过调控MYC表达抑制甲状腺癌细胞的增殖；5）SOSTDC1在甲状腺癌中表达下调并通过下调cyclin A2和cyclin E2的表达抑制细胞增殖。