STIM1作为代谢检查点调控肝癌发生与转移

Cancer cells possess anabolic pathways to acquire energy and material basis for rapid tumor growth, while the metastatic tumor cells prefer catabolic metabolism to survive under metabolic stress. However, the metabolic reprogramming in cancer cells orchestrating tumorigenesis and metastasis is unknown. Here, we show that stromal interaction molecule 1 (STIM1), an endoplasmic reticulum (ER) Ca2+ sensor, mediates dynamic metabolic-switching during the tumorigenesis and metastasis of hepatocellular carcinoma (HCC). During tumorigenesis, STIM1 correlates with elevated HIF-1α in hypoxic HCC and is upregulated during tumor growth. HIF-1 transcripts STIM1 and promotes store-operated calcium entry (SOCE), which in return contributes to the stabilization of HIF-1α by activating Ca2+ /calmodulin-dependent protein kinase II (CaM kinase II or CaMKII) and p300 in hypoxic HCC cells. Moreover, STIM1-deficiency inhibits cell proliferation via repressing HIF-1-dependent anabolic metabolism, such as glucose uptake, glycolysis and fatty acid synthesis (FAS), while activates LKB1(Liver kinase B1)/AMPK(AMP-activated protein kinase)-dependent fatty acid oxidation (FAO). Of interest, STIM1 is significantly down-regulated in invasion-edge compared to the corresponding center region of HCC tumor tissue, as well as decreased in several epithelial-mesenchymal transition (EMT) models of HCC cells. Bioinformatics analysis reveals that low expression of STIM1 is closely associated with poor-survival of HCC patients. Mechanistically, STIM1 stabilizes Snai1 by activating SOCE/CaMKII/PI3K/GSK3β signaling cascade during carcinogenesis, whereas Snai1 transcriptionally suppresses STIM1 expression and represses SOCE during EMT. Low concentration of SOCE inhibitor SKF96365 notably promotes the metastasis and anoikis-resistance of Snai1 O/E-cells. On the contrary, restoration of STIM1 dramatically diminishes the anoikis-resistance and metastatic ability. These cells exhibit reduced anabolic metabolism and activated FAO induced by Snai1-O/E in HCC cells. These results suggest that STIM1 is a metabolic checkpoint that programs tumorigenesis and metastasis of HCC via temporally regulating the anabolic/catabolic balance to meet the dynamic metabolic requirements.

546 2020-11-06
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