Wu Bo, Wang Yi, Yang Xiang-Min, Xu Bao-Qing, Feng Fei, Wang Bin, Liang Qiang, Li Yu, Zhou Yang, Jiang Jian-Li, Chen Zhi-Nan
Cell Engineering Research Centre & Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, 169 Changle West Road, Xi'an, 710032, P. R. China.
J Exp Clin Cancer Res. 2015 Oct 6;34:110. doi: 10.1186/s13046-015-0226-6.
Dysregulated endocytosis of membrane proteins contributes significantly to several hallmarks of cancer. Basigin can enhance cancer progression, but its precise mechanism remains unclear. CD98 promotes cell spreading and tumorigenicity by triggering integrin clustering and enhancing cell adhesion to the extracellular matrix. The endocytosis and recyle of basigin and CD98 might play critical roles in cancer.
The role of CD98 was confirmed in liver cancer cells by cell spreading in vitro and tumorigenicity by nude mice xenograft tumor assay in vivo; membrane expression of basigin and CD98 in SMMC-7721 was measured by FCAS; pull down and SPR analysis were uses to reveal the direct association between basigin and CD98; DsRed1 tagged CD98 was blocked in the cytoplasm in K7721 (whose basigin was knockn out) and had a well colocalization with ER and Rab5a positive recycling endosomes under co-focal; finally, by FRET imaging and FCAS we observed the internalization of basigin and CD98 was flotillin-1-regulated, and their recycle at early steps was Arf6-mediated.
Basigin and CD98 were highly expressed and co-localized on the human hepatocellular carcinoma (HCC) cell membrane; basigin can directly bind to CD98, mediating CD98 redistribution on the HCC cell membrane and activating the downstream integrin signaling pathway. Internalization of basigin and CD98 was flotillin-1 regulated the and their recycling was mediated by Arf6. This recycling process for basigin and CD98 promotes cell spreading and tumor growth in liver cancer xenografts.
Basigin, as a redistribution chaperone of CD98, plays a critical role in promoting cell spreading and the progression of hepatocellular carcinoma.
膜蛋白内吞作用失调在癌症的多个特征中起重要作用。基底膜蛋白可促进癌症进展，但其确切机制尚不清楚。CD98通过触发整合素聚集和增强细胞与细胞外基质的黏附来促进细胞铺展和肿瘤发生。基底膜蛋白和CD98的内吞及再循环可能在癌症中起关键作用。
通过体外细胞铺展和体内裸鼠异种移植瘤实验检测肿瘤发生能力，证实CD98在肝癌细胞中的作用；采用流式细胞术检测SMMC-7721中基底膜蛋白和CD98的膜表达；通过下拉实验和表面等离子体共振分析揭示基底膜蛋白与CD98之间的直接关联；在K7721细胞（基底膜蛋白基因敲除）中，DsRed1标记的CD98被阻断在细胞质中，在共聚焦显微镜下与内质网和Rab5a阳性再循环内体共定位良好；最后，通过荧光共振能量转移成像和流式细胞术观察到基底膜蛋白和CD98的内化受小窝蛋白-1调节，其早期再循环由Arf6介导。
基底膜蛋白和CD98在人肝癌细胞膜上高表达且共定位；基底膜蛋白可直接与CD98结合，介导CD98在肝癌细胞膜上的重新分布并激活下游整合素信号通路。基底膜蛋白和CD98的内化受小窝蛋白-1调节，其再循环由Arf6介导。基底膜蛋白和CD98的这种再循环过程促进肝癌异种移植瘤中的细胞铺展和肿瘤生长。
基底膜蛋白作为CD98的重新分布伴侣，在促进细胞铺展和肝细胞癌进展中起关键作用。
