Stim1-flox Mouse

STIM1, or stromal interaction molecule 1, is a key component of the store-operated Ca2+ entry (SOCE) pathway. It is located on the endoplasmic reticulum membrane and functions as a Ca2+ sensor of the endoplasmic reticulum Ca2+ store [1,3,4,5,6]. In non-excitable cells, STIM1, along with Orai1 in the plasma membrane, forms the highly Ca2+ selective CRAC channel. When intracellular Ca2+ stores in the endoplasmic reticulum are depleted, STIM1 senses this change and triggers the opening of Orai1 channels, allowing Ca2+ entry. This process is crucial for initiating diverse signalling cascades involved in essential cellular processes like gene regulation, cell growth and death, secretion, and gene transcription [1].

In hepatocellular carcinoma (HCC), STIM1 knockout-HCC cells generated by CRISPR-Cas9 were used to study its role. Results showed that STIM1 was down-regulated in metastatic HCC cells. Low STIM1 levels were associated with poor outcomes for HCC patients. During tumor growth, STIM1 stabilized Snail1 protein through the CaMKII/AKT/GSK-3β pathway, while during metastasis, upregulated Snail1 suppressed STIM1/SOCE. Restoration of STIM1 diminished anoikis-resistance and metastasis induced by Snail1. Mechanistically, downregulated STIM1 shifted the metabolic balance from aerobic glycolysis towards AMPK-activated fatty acid oxidation, contributing to Snail1-driven metastasis and anoikis-resistance [2].

In conclusion, STIM1 is essential for maintaining Ca2+ homeostasis and regulating various cellular functions through the SOCE pathway. Its role in diseases such as HCC, as revealed by gene knockout models, shows that it can act as a metabolic checkpoint regulating tumor invasion and metastasis. Understanding STIM1's functions through model-based research provides insights into the underlying mechanisms of diseases and may offer potential therapeutic targets.