CD147 reinforces [Ca(2+)](i) oscillations and promotes oncogenic progression in hepatocellular carcinoma

Oscillations in intracellular Ca(2+) concentrations ([Ca(2+)](i)) mediate various cellular function. Although it is known that [Ca(2+)](i) oscillations are susceptible to dysregulation in tumors, the tumor-specific regulators of [Ca(2+)](i) oscillations are poorly characterized. We discovered that CD147 promotes hepatocellular carcinoma (HCC) metastasis and proliferation by enhancing the amplitude and frequency of [Ca(2+)](i) oscillations in HCC cells. CD147 activates two distinct signaling pathways to regulate [Ca(2+)](i) oscillations. By activating FAK-Src-IP3R1 signaling pathway, CD147 promotes Ca(2+) release from endoplasmic reticulum (ER) and enhances the amplitude of [Ca(2+)](i) oscillations. Furthermore, CD147 accelerates ER Ca(2+) refilling and enhances the frequency of [Ca(2+)](i) oscillations through activating CaMKP-PAK1-PP2A-PLB-SERCA signaling pathway. Besides, CD147-promoted ER Ca(2+) release and refilling are tightly regulated by changing [Ca(2+)](i). CD147 may activate IP3R1 channel under low [Ca(2+)](i) conditions and CD147 may activate SERCA pump under high [Ca(2+)](i) conditions. CD147 deletion suppresses HCC tumorigenesis and increases the survival rate of liver-specific CD147 knockout mice by regulating [Ca(2+)](i) oscillations in vivo. Together, these results reveal that CD147 functions as a critical regulator of ER-dependent [Ca(2+)](i) oscillations to promote oncogenic progression in HCC.