biostudies-literatureSun CNHLBI NIH HHS396https://www.ebi.ac.uk/biostudies/studies/S-EPMC6529459biostudies-literatureUnknown10(6)Ca²⁺ oscillation is a system-level property of the cellular Ca²⁺-handling machinery and encodes diverse physiological and pathological signals. The present study tests the hypothesis that Ca²⁺ oscillations play a vital role in maintaining the stemness of liver cancer stem cells (CSCs), which are postulated to be responsible for cancer initiation and progression. We found that niche factor-stimulated Ca²⁺ oscillation is a signature feature of CSC-enriched Hep-12 cells and purified α2δ1⁺ CSC fractions from hepatocellular carcinoma cell lines. In Hep-12 cells, the Ca²⁺ oscillation frequency positively correlated with the self-renewal potential. Using a newly developed high signal, endoplasmic reticulum (ER) localized Ca²⁺ sensor GCaMP-ER2, we demonstrated CSC-distinctive oscillatory ER Ca²⁺ release controlled by the type 2 inositol 1,4,5-trisphosphate receptor (IP₃R2). Knockdown of IP₃R2 severely suppressed the self-renewal capacity of liver CSCs. We propose that targeting the IP₃R2-mediated Ca²⁺ oscillation in CSCs might afford a novel, physiologically inspired anti-tumor strategy for liver cancer.Cell death & diseaseCentral role of IP₃R2-mediated Ca²⁺ oscillation in self-renewal of liver cancer stem cells elucidated by high-signal ER sensor.PMC6529459R24 HL120847Liu HLee JCDoran RSun CZhao WSun TKotlikoff MILi WLee FKZhang ZShui BShen QSWang XReining SCheng HfalseCentral role of IP₃R2-mediated Ca²⁺ oscillation in self-renewal of liver cancer stem cells elucidated by high-signal ER sensor.Ca²⁺ oscillation is a system-level property of the cellular Ca²⁺-handling machinery and encodes diverse physiological and pathological signals. The present study tests the hypothesis that Ca²⁺ oscillations play a vital role in maintaining the stemness of liver cancer stem cells (CSCs), which are postulated to be responsible for cancer initiation and progression. We found that niche factor-stimulated Ca²⁺ oscillation is a signature feature of CSC-enriched Hep-12 cells and purified α2δ1⁺ CSC fractions from hepatocellular carcinoma cell lines. In Hep-12 cells, the Ca²⁺ oscillation frequency positively correlated with the self-renewal potential. Using a newly developed high signal, endoplasmic reticulum (ER) localized Ca²⁺ sensor GCaMP-ER2, we demonstrated CSC-distinctive oscillatory ER Ca²⁺ release controlled by the type 2 inositol 1,4,5-trisphosphate receptor (IP₃R2). Knockdown of IP₃R2 severely suppressed the self-renewal capacity of liver CSCs. We propose that targeting the IP₃R2-mediated Ca²⁺ oscillation in CSCs might afford a novel, physiologically inspired anti-tumor strategy for liver cancer.2019-01-01T00:00:00Z2019 May2024-11-12T03:04:08.789Z2019-06-06T23:18:17ZS-EPMC65294593111396110.1038/s41419-019-1613-2