Central role of IP3R2-mediated Ca2+ oscillation in self-renewal of liver cancer stem cells elucidated by high-signal ER sensor

Abstract

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.