CXCR4基因沉默对黑色素瘤侵袭和转移影响的实验研究
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摘要
侵袭和转移是影响黑色素瘤患者生存的首要因素,也是其治疗的最大障碍。SDF-1/CXCR4生物轴作为少数具有点对点精确传导生物信息的生物轴系统之一,在多数肿瘤的侵袭和转移中发挥重要作用。越来越多的研究表明,趋化因子受体CXCR4(Chemokine receptor CXCR4)参与肿瘤侵袭和转移的多个关键环节。本研究利用RNA干扰技术下调趋化因子受体CXCR4基因的表达,探讨CXCR4基因沉默对黑色素瘤及细胞系体外侵袭及转移的影响及机制。设计合成CXCR4特异性短发夹状RNA(shRNA)插入pSilencer载体,转染人高转移性黑色素瘤细胞株MV3,RT-PCR和Western blot检测shRNA对靶基因CXCR4表达的影响。利用Transwell小室模型检测细胞体外侵袭能力,MTT检测细胞增殖状况。通过裸鼠尾静脉瘤细胞注射方法,构建黑色素瘤转移模型,检测CXCR4基因沉默对黑色素瘤转移能力的影响。研究证实,在人转移性黑色素瘤细胞系、人黑色素瘤原发灶及转移组织内均存在CXCR4选择性高表达;实验成功构建并筛选出CXCR4特异性shRNA质粒载体,结果表明,以CXCR4为靶向的shRNA能够有效下调CXCR4基因的表达,降低黑色素瘤细胞增殖、体外侵袭及转移能力。提示CXCR4是黑色素瘤侵袭和转移过程中的重要调控因子,为黑色素瘤的生物治疗提供了新的靶分子并奠定实验基础。
Invasion and metastasis are the main factors to affect the survival of the patients with melanoma. SDF-1/CXCR4 singnaling pathway plays an important role in the invasion and metastasis of many tumors. This study is to construct a CXCR4 specific recombinant plasmid vector and to research its inhibiting effect on invasion capacity in vitro of human melanoma MV3 cell line and its metastasis potential in mude mice. A CXCR4 specific recombinant plasmid vector was constructed and transfected into the cultured MV3 cell line with lipofectamine. RT-PCR and then Western blot were used to detect the mRNA and protein expression of CXCR4. Invasion capability in vitro of the cells was evaluated by Transwell chamber. The cell proliferation capacity was detected by MTT method. The nude mouse model of metastasis was established by injection of MV3 cells into the tail vein. The results showed that both the CXCR4 mRNA and protein expression rate in the CXCR4-shRNA group were significantly lower than that of the control group. CXCR4 silenced with shRNA lead to a significant decrease in the capacity of the invasion and proliferation of melanoma cell in vitro. Moreover, melanoma cells with CXCR4 shRNA permanant transfection had much lower metastatic potential in nude mice than control cells and mock control cells in vivo. The study indicates that CXCR4 shRNA can inhibit the expression of CXCR4 and decrease the invasion and metastatic potential of melanoma, and CXCR4 may be an important factor or therapeutic target of melanoma.
Invasion and metastasis are the main factors to affect the survival of the patients with melanoma. SDF-1/CXCR4 singnaling pathway plays an important role in the invasion and metastasis of many tumors. This study is to construct a CXCR4 specific recombinant plasmid vector and to research its inhibiting effect on invasion capacity in vitro of human melanoma MV3 cell line and its metastasis potential in mude mice. A CXCR4 specific recombinant plasmid vector was constructed and transfected into the cultured MV3 cell line with lipofectamine. RT-PCR and then Western blot were used to detect the mRNA and protein expression of CXCR4. Invasion capability in vitro of the cells was evaluated by Transwell chamber. The cell proliferation capacity was detected by MTT method. The nude mouse model of metastasis was established by injection of MV3 cells into the tail vein. The results showed that both the CXCR4 mRNA and protein expression rate in the CXCR4-shRNA group were significantly lower than that of the control group. CXCR4 silenced with shRNA lead to a significant decrease in the capacity of the invasion and proliferation of melanoma cell in vitro. Moreover, melanoma cells with CXCR4 shRNA permanant transfection had much lower metastatic potential in nude mice than control cells and mock control cells in vivo. The study indicates that CXCR4 shRNA can inhibit the expression of CXCR4 and decrease the invasion and metastatic potential of melanoma, and CXCR4 may be an important factor or therapeutic target of melanoma.
引文
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