CD147通过IGFBP2调控恶性黑素瘤凋亡的作用机制研究

Malignant Melanoma, one of the most malignant cutaneous tumors, is characterized by its high potential for invasiveness and metastasis. And apoptosis of the tumor is the key to the inhibition of tumor growth, reversal of tumor drug resistance, and treatment of tumor.Studies have discovered that the human cell-surface molecule CD147, an integral plasma membrane glycoprotein belonging to the Ig superfamily, is highly expressed on the surface of various tumor cells. It stimulates the production of multiple matrix metalloproteinases (MMPs) by tumor cells and fibroblasts, serving as a key regulator of tumor cell invasiveness and metastasis. In addition, there is growing evidence that CD147 may regulate the apoptosis of tumour cells, but the mechanism is still unknown. In our study, We successfully established a stable CD147 shRNA A375 cell line to explore the mechanism.And Human Apoptosis Antibody Array tested the total protein of these two cell lines, and found 9 apoptosis related protein, such as IGFBP2 (Insulin-like Growth Factor Binding Protein 2）etc .Further,we will use cell、animal models、Malignant melanoma tissue microarray to explore the correlation and the mechanismbetween CD147 and IGFBP2. We demonstrate that whether CD147 may represent a novel therapeutic target to treat malignant melanoma clinically.

恶性黑素瘤是一种恶性程度较高的肿瘤，其临床放化疗治疗疗效并不理想，而恶性黑素瘤本身的抗凋亡性质可能是其对放化疗不敏感的主要因素之一。本课题组长期致力于CD147 分子在皮肤肿瘤中的研究，近来发现CD147参与了恶性黑素瘤细胞的凋亡，但具体机制仍不明确。申请人博士期间通过人凋亡抗体芯片首次筛选出了与CD147相关的凋亡蛋白IGFBP2，并进行了CD147和IGFBP2在皮肤恶性黑素瘤细胞和裸鼠皮下成瘤模型中的初步研究。本课题将通过细胞、裸鼠皮下成瘤模型和人恶性黑素瘤组织来进一步探讨CD147和IGFBP2在恶性黑素瘤凋亡中的相互关系，以及CD147通过IGFBP2调控恶性黑素瘤凋亡的具体机制。本研究旨在明确CD147和IGFBP2分子在皮肤恶性黑素瘤凋亡中的作用及机制，为临床恶性黑素瘤治疗提供新的靶分子和治疗策略。

恶性黑素瘤(malignant melanoma, MM)是一种恶性程度较高的肿瘤，其临床放化疗治疗疗效并不理想，而恶性黑素瘤本身的抗凋亡性质可能是其对放化疗不敏感的主要因素之一。本研究旨在明确CD147和IGFBP2分子在皮肤恶性黑素瘤凋亡中的作用及机制，为临床恶性黑素瘤抗凋亡治疗提供新的靶分子和治疗策略。. 本研究中，我们首先建立了CD147敲降的皮肤MM（A375-sh-CD147）细胞株，明确了CD147干扰对A375细胞凋亡的影响；通过人凋亡抗体芯片，找出了与CD147相互作用的凋亡相关蛋白谱，在这一系列蛋白中IGFBP2（Insulin-like Growth Factor Binding Protein 2）受CD147调控最显著；我们随后证实了CD147可以通过Akt/mTOR途径调控IGFBP2的表达，进而介导MM细胞的凋亡；同时通过裸鼠皮下成瘤模型进一步在体内水平明确CD147-IGFBP2与凋亡的相互关系。最后，我们利用MM组织芯片，在大样本量临床组织中证实了CD147和IGFBP2表达的相关性。. 本研究揭示CD147可能是通过Akt/mTOR途径来调控IGFBP2。CD147—Akt/mTOR—IGFBP2—MM细胞凋亡，这一通路的发现，进一步揭示CD147的凋亡机制，也为临床治疗恶性黑色素瘤的药物研发和多药耐药提供了新的思路和新的靶点。