CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma.
CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma.
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CD147 增强 [Ca2](i) 振荡并促进肝细胞癌的致癌进展
DOI：
10.18632/oncotarget.5225
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发表时间：
2015-10-27
期刊：
影响因子：
--
通讯作者：
Chen ZN
中科院分区：
文献类型：
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作者：
Tang J;Guo YS;Yu XL;Huang W;Zheng M;Zhou YH;Nan G;Wang JC;Yang HJ;Yu JM;Jiang JL;Chen ZN
细胞内Ca 2+浓度（[Ca 2 +]i）的振荡介导各种细胞功能。虽然已知[Ca 2 +]i振荡对肿瘤中的失调敏感，但[Ca 2 +]i振荡的肿瘤特异性调节剂的特征很差。我们发现CD 147通过增强肝癌细胞内[Ca 2 +]i振荡的幅度和频率来促进肝癌细胞的转移和增殖。CD 147激活两种不同的信号通路来调节[Ca 2 +]i振荡。CD 147通过激活FAK-Src-IP 3R 1信号通路，促进内质网Ca ~（2+）释放，增强[Ca ~（2+）]i振荡幅度。此外，CD 147还通过激活CaMKP-PAK 1-PP 2A-PLB-SERCA信号通路，促进内质网Ca ~（2+）再充盈，提高[Ca ~（2+）]i振荡频率。此外，CD 147促进的内质网Ca ~（2+）释放和再填充受[Ca ~（2+）]i的调节。在低[Ca 2 +]i条件下，CD 147可激活IP 3R 1通道，在高[Ca 2 +]i条件下，CD 147可激活SERCA泵。CD 147缺失抑制肝癌的发生并通过调节体内[Ca 2 +]i振荡增加肝脏特异性CD 147敲除小鼠的存活率总之，这些结果表明，CD 147作为ER依赖性[Ca 2 +]i振荡的关键调节因子发挥作用，以促进HCC的致癌进展。
Oscillations in intracellular Ca2+ concentrations ([Ca2+]i) mediate various cellular function. Although it is known that [Ca2+]i oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca2+]i oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca2+]i oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca2+]i oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca2+ release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca2+]i oscillations. Furthermore, CD147 accelerates ER Ca2+ refilling and enhances the frequency of [Ca2+]i oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca2+ release and refilling are tightly regulated by changing [Ca2+]i. CD147 may activate IP3R1 channel under low [Ca2+]i conditions and CD147 may activate SERCA pump under high [Ca2+]i conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca2+]i oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca2+]i oscillations to promote oncogenic progression in HCC.