NIBP在人结肠癌侵袭转移中对NIK/IKK/NF-κB信号通路的作用及其机制的研究

Activation of NIK/IKK/NF-κB signaling pathway plays an important role in cell proliferation, anti-apoptosis, angiogenesis and cancer metastasis, NIK and IKK are two key factors in this pathway. NBIP is a novel protein which can bind NIK and IKKβ. Recent studies showed that the expression of NIBP was up-regulated in human colon cancer and our data also indicated that NIBP may involve to the colon cancer metastasis and activation of NF-κB. Thus, it is considerated that NIBP probably play roles in colon cancer metastasis through regulating NIK/IKK/NF-κB signal pathway. In this study, the expression of NIBP and some factors which involved in NIK/IKK/NF-κB signal pathway in normal colonic mucosa, colon adenoma and colon cancer would be investigated. In addition, the effects of NIBP in NIK/IKK/NF-κB signal pathway in colon cancer metastasis would be studied by gene engineering technology and the orthotopic transplantation tumor model. This study will elusidate some mechanisms of colon cancer invasion and metastasis and provide the experimental basis for exploring new therapeutic target on human colon carcinama.

研究证实，NF-κB的激活在对抗细胞凋亡、稳定肿瘤细胞微环境、促肿瘤细胞生长、侵袭转移过程中发挥重要作用，其中NIK和IKK是NF-κB激活通路中两个最主要的生物分子。而NIBP是新近发现的一种能与NIK及IKKβ结合的支架蛋白。已有报道结肠癌组织中NIBP表达增高，另外我们的前期研究亦发现NIBP的表达与人结肠癌的NF-κB活化及侵袭转移密切相关。因此我们推测NIBP可能通过调控NIK/IKK/NF-κB信号通路在人结肠癌的侵袭转移过程发挥关键作用。本研究拟检测正常结肠粘膜、结肠腺瘤以及结肠癌患者的血清及结肠组织中NIBP与NIK/IKK/NF-κB信号通路激活相关因子的表达，同时采用基因工程技术及原位移植瘤模型等方法探讨NIBP表达变化对NIK/IKK/NF-κB信号通路及细胞侵袭转移能力的影响，为阐明人结肠癌侵袭转移机制，寻找治疗结肠癌新靶点提供实验依据。

NIBP是调节NF-κB信号通路活性，在对抗细胞凋亡、稳定肿瘤细胞微环境、促肿瘤细胞生长、侵袭转移过程中发挥重要作用。我们的研究发现：（1）结肠癌组织中NIBP、p-p65、VEGF、ICAM-1、MMP2、MMP9的阳性率表达均高于结肠腺瘤和正常结肠黏膜组织，且NIBP、p-p65、VEGF、ICAM-1、MMP2、MMP9在结肠癌组织中的表达与浸润深度、TNM临床分期、淋巴结转移和远处转移有关。（2）利用基因工程技术调控NIBP在人结肠癌细胞中的表达（过表达/低表达），通过体外细胞实验和裸鼠原位移植瘤实验发现，NIBP在人结肠癌细胞中可能是连接NF-κB信号通路的桥梁，进而调控结肠癌细胞的侵袭能力。（3）通过对NIBP低表达的结肠癌细胞进行研究发现，靶向下调NIBP基因表达可抑制人结肠癌HCT116 细胞EMT的发生。因此，通过本研究我们认为：（1）NIBP可能通过调控NF-κB经典通路的活化影响人结肠癌的侵袭转移。（2）NIBP可能通过调控NF-κB经典通路和非经典通路来影响结肠癌细胞EMT的发生。