CD147 reinforces [Ca2+]i oscillations and promotes oncogenic progression in hepatocellular carcinoma.
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.
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.
Juan
J
Tang
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.
Yun-Shan
YS
Guo
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.
Xiao-Ling
XL
Yu
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.
Wan
W
Huang
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.
Ming
M
Zheng
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.
Ying-Hui
YH
Zhou
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.
Gang
G
Nan
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.
Jian-Chao
JC
Wang
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.
Hai-Jiao
HJ
Yang
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.
Jing-Min
JM
Yu
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.
Jian-Li
JL
Jiang
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.
Zhi-Nan
ZN
Chen
D000818:Animals; D051926:Basigin / Q000378:metabolism*; D015153:Blotting, Western; D020013:Calcium Signaling / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D018450:Disease Progression; D055785:Gene Knockdown Techniques; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000473:pathology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D034741:RNA, Small Interfering; D051926:Basigin
CD147; [Ca2+]i oscillations; hepatocellular carcinoma