Central role of IP(3)R2-mediated Ca(2+) oscillation in self-renewal of liver cancer stem cells elucidated by high-signal ER sensor

Ca(2+) oscillation is a system-level property of the cellular Ca(2+)-handling machinery and encodes diverse physiological and pathological signals. The present study tests the hypothesis that Ca(2+) 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 Ca(2+) 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 Ca(2+) oscillation frequency positively correlated with the self-renewal potential. Using a newly developed high signal, endoplasmic reticulum (ER) localized Ca(2+) sensor GCaMP-ER2, we demonstrated CSC-distinctive oscillatory ER Ca(2+) release controlled by the type 2 inositol 1,4,5-trisphosphate receptor (IP(3)R2). Knockdown of IP(3)R2 severely suppressed the self-renewal capacity of liver CSCs. We propose that targeting the IP(3)R2-mediated Ca(2+) oscillation in CSCs might afford a novel, physiologically inspired anti-tumor strategy for liver cancer.