A CD147-targeting siRNA inhibits the proliferation, invasiveness and VEGF production of human malignant melanoma cells by down-regulating glycolysis

Cancer cells require glycolysis for energy; this results in excessive lactate production and secretion. Lactate, the end product of glycolysis, reduces the extracellular pH and contributes to the proliferation, invasiveness, metastasis, and angiogenesis of tumor cells. Our previous results revealed that the over-expressed CD147/basigin plays a critical role in malignant melanoma (MM) invasiveness, metastasis and angiogenesis: CD147 has also been implicated in a specific and strong interaction with monocarboxylate transporters (MCT) 1 and 4 that mediate the transport of lactate. In the present study, we investigated whether CD147/basigin is involved, via its association with MCT1 and 4 to transport lactate, in glycolysis and then contributes to the progression of A375 melanoma cells. A375 cells expressed remarkably higher CD147, MM and 4 and showed increased glycolysis rate compared with normal human melanocytes (NHMC). CD147/basigin co-localized with MCT1 and 4 in the A375 cell membrane. Furthermore, silencing of CD147/basigin in A375 cells by a siRNA clearly abrogated the expression of MCT1 and 4 and their co-localization with CD147/basigin and dramatically decreased the glycolysis rate, extracellular pH, and the production of ATP. Thus, cell proliferation, invasiveness, and VEGF production were significantly decreased by siRNA. These results strongly suggest that highly-expressed CD147 interacts with MCT1 and 4 to promote tumor cell glycolysis, resulting in the progression of MM. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

癌细胞需要糖酵解来获取能量；这会导致乳酸产生和分泌过多。乳酸是糖酵解的终产物，它会降低细胞外pH值，并有助于肿瘤细胞的增殖、侵袭、转移和血管生成。我们之前的研究结果显示，过度表达的CD147/ basigin在恶性黑色素瘤（MM）的侵袭、转移和血管生成中起着关键作用：CD147还与单羧酸转运蛋白（MCT）1和4有特定且强烈的相互作用，而MCT1和4介导乳酸的转运。在本研究中，我们探讨了CD147/ basigin是否通过与MCT1和4结合来转运乳酸从而参与糖酵解，并进而促进A375黑色素瘤细胞的进展。与正常人黑素细胞（NHMC）相比，A375细胞显著高表达CD147、MCT1和MCT4，且糖酵解速率增加。CD147/ basigin与MCT1和4在A375细胞膜上共定位。此外，通过小干扰RNA（siRNA）沉默A375细胞中的CD147/ basigin，明显消除了MCT1和4的表达以及它们与CD147/ basigin的共定位，并显著降低了糖酵解速率、细胞外pH值和三磷酸腺苷（ATP）的产生。因此，通过siRNA，细胞增殖、侵袭和血管内皮生长因子（VEGF）的产生显著减少。这些结果有力地表明，高表达的CD147与MCT1和4相互作用促进肿瘤细胞糖酵解，从而导致MM的进展。（C）2008爱思唯尔爱尔兰有限公司。保留所有权利。