CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma
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Juan Tang1,*, Yun-Shan Guo1,*, Xiao-Ling Yu1,*, Wan Huang1,*, Ming Zheng1, Ying-Hui Zhou1, Gang Nan1, Jian-Chao Wang1, Hai-Jiao Yang1, Jing-Min Yu1, Jian-Li Jiang1 and Zhi-Nan Chen1
1 Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer Biology, State Key Discipline of Cell Biology, Fourth Military Medical University, Xi’an, China
* These authors have contributed equally to this work
Zhi-Nan Chen, email:
Jian-Li Jiang, email:
Keywords: hepatocellular carcinoma; CD147; [Ca2+]i oscillations
Received: April 06, 2015 Accepted: August 11, 2015 Published: October 19, 2015
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.
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