CD147在垂体腺瘤侵袭性发生中的作用和机制研究

Pituitary tumor is one of the most common intracranial tumors, although benign, a considerable part possesses invasiveness, but detailed mechanism is unknown. CD147 is a novel transmembrane glycoprotein, and one of the gene targerts in a variety of tumor cells. In previous investigation, we confirmed that CD147 protein expression be associated with those of MMP-2, MMP-9, adenoma invasiveness and prognosis. And a recent study found that CD147-CyPA interactions played an important role in tumor invasiveness, suggesting that CD147-CyPA play a certain role in the adenoma invasion. This research would determined by histochemical first that CyPA would be associated with adenomas invasion, CD147 expression.Lentiviral vectors with small interferring RNA specific targeting CD147 or CyPA gene would be built, then were transfected cells and tumor proliferation, invasion and downstream gene expression were observed. Finally, lentiviral vectors were injected to pituitary adenomas in a pituitary tumor animal models, and whether CD147 and CyPA siRNA can decrease the body or inhibit pituitary tumor cell growth and invasion was observed. Thus the role and mechanism of CD147 in invasive pituitary tumors would be confirmed and provide new ideas and targets for the prevention and treatment of invasive pituitary tumors .

垂体瘤是颅内最常见的肿瘤之一，虽属良性，但相当部分具有侵袭性，具体机制不明。CD147是一种新型跨膜糖蛋白，并在多种肿瘤细胞中研究确定其是肿瘤基因治疗的适合靶点之一，我们在先前课题中证实CD147与垂体腺瘤MMP-2、MMP-9蛋白的表达、腺瘤的侵袭性及预后相关。且近年研究发现CD147-CyPA相互作用在肿瘤侵袭性中发挥重要作用，因此推测CD147-CyPA在腺瘤侵袭性中发挥作用。本课题先通过组化确定CyPA与腺瘤侵袭性、CD147相关，构建特异靶向CD147、CyPA 基因的小干扰RNA慢病毒载体，转染细胞，观察肿瘤增殖、侵袭及下游基因的表达情况等；最后，注射慢病毒载体至动物模型的垂体瘤周围，观察CD147 及CyPA siRNA是否能在体内缓解或抑制垂体瘤细胞的生长及侵袭，从而明确CD147在垂体瘤侵袭性发生的作用和机制，为侵袭性垂体瘤的防治提供新的思路和靶点。

虽然垂体腺瘤绝大部分属于良性肿瘤，但部分肿瘤向鞍区周围组织浸润生长，破坏正常结构，被称为侵袭性垂体腺瘤，目前有多种机制假说，但具体机制不明。CD147是一种新型跨膜糖蛋白，并在多种肿瘤细胞中研究确定其是肿瘤基因治疗的适合靶点之一，本课题在先前课题中证实CD147与垂体腺瘤MMP-2、MMP-9蛋白的表达、腺瘤的侵袭性及预后相关的基础上，先通过组化、western blot确定CyPA与腺瘤侵袭性、MMP-9表达相关，然后构建特异靶向CD147、CyPA 基因的小干扰RNA慢病毒载体，转染GH3细胞，发现通过siRNA干扰CypA表达可有效提高抑瘤效应。抑制CypA也抑制下游基因MMP-9的表达，抑制CypA可能通过ERK1/2信号通路抑制GH3细胞的增殖，促进GH3细胞的凋亡。通过siRNA CD147慢病毒抑制CD147表达，能抑制GH3细胞的生长与增殖，而增加GH3细胞的凋亡。最后，将优化的siRNA-CypA，siRNA-CD147慢病毒分别注入成瘤的雌性裸鼠动物模型肿瘤中，发现均能不同程度抑制肿瘤的生长。本研究进一步提示CD147 及CyPA 参与了垂体瘤细胞的生长及侵袭，从而揭示垂体瘤侵袭性发生的可能作用机制，将对垂体瘤侵袭性发生的病理生理机制研究、临床诊断及治疗具有重要意义。