CTGF-αvβ5 integrin/FAK/PI3K/AKT-转录因子-miR-18a/b反馈环路调控鼻咽癌发病过程

Our previous preliminary investigation suggested that CTGF was taken as a tumor suppressor participating in the pathogenesis of nasopharyngeal carcinoma. Further, miRNA array and real-time PCR were used to confirm diffenentially expressed miRNAs in knocking down the expression of CTGF in NPC cells, and miR-18a and miR-18b were shown to be upregulated. Based on the fact that CTGF was not only the directed regulation target of miR-18a, but also the predicted regulation target of miR-18b, we speculated the existence of feedback-regulated loop between CTGF and miR-18a/b in NPC. Therefore, further studies will be performed as follow: 1) Confirming the role of tumor suppressor of CTGF in NPC. 2) Identifying αvβ5 integrin/FAK/PI3K/Akt pathway mediated by CTGF to control the expression of transcription factors, which therefore affects the expression of miR-18a/b. 3) Validating transcription factors to control the expression of miR-18a/b through directly regulating their promoter. 4) Confirming the expression changes of transcription factors were regulated by miR-18a/b through CTGF-mediated αvβ5 integrin/FAK/PI3K/Akt pathway, which may form a possible feedback loop of regulation.

前期我们初步鉴定CTGF可能作为抑癌基因参与了鼻咽癌发病过程。miRNA array和real-time PCR分析发现，在鼻咽癌细胞中抑制CTGF表达后显著上调miR-18a和miR-18b。由于CTGF不但是miR-18a的直接调节靶基因，而且也是miR-18b预测调节靶标，我们推测CTGF与miR-18a/b之间在鼻咽癌中存在着反馈调节环路。进一步研究将从如下几个方面开展工作：1）确证CTGF在鼻咽癌中发挥抑癌基因的功能；2）明确CTGF经αvβ5 integrin/FAK/PI3K/Akt 信号通路影响转录因子表达来调控miR-18a/b的表达；3）验证转录因子可以通过直接调节miR-18a/b启动子来影响它们转录；4）明确miR-18a/b可以直接经CTGF调节αvβ5 integrin/FAK/PI3K/Akt信号通路影响转录因子表达，从而形成反馈环路调控途径。

在本次研究中，我们首先发现了CTGF在鼻咽癌中发挥了候选抑癌基因的作用，并不类似其在其它肿瘤中发挥了癌基因作用。其次，我们确定了CTGF在鼻咽癌中通过抑制PI3K/AKT信号，降低了转录因子c-Jun和c-Myc表达，从而抑制miR-18b表达，进而，解除了对CTGF表达的抑制，从而形成了一条负性反馈环路，参与调控鼻咽癌细胞生成。除此之外，CTGF还能通过调控FAK/PI3K/AKT信号，从而抑制EMT信号，从而抑制鼻咽癌细胞的游走和侵袭。我们的研究为鼻咽癌发病分子机理提供一个新的思路，并可能为鼻咽癌靶向基因治疗奠定新的理论基础。