Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
Theranostics. 2020 May 16;10(14):6483-6499. doi: 10.7150/thno.44025. eCollection 2020.
: Cancer cells undergoing invasion and metastasis possess a phenotype with attenuated glycolysis, but enhanced fatty acid oxidation (FAO). Calcium (Ca)-mediated signaling pathways are implicated in tumor metastasis and metabolism regulation. Stromal-interaction molecule 1 (STIM1) triggered store-operated Ca entry (SOCE) is the major route of Ca influx for non-excitable cells including hepatocellular carcinoma (HCC) cells. However, whether and how STIM1 regulates the invasion and metastasis of HCC metabolic reprogramming is unclear. : The expressions of STIM1 and Snail1 in the HCC tissues and cells were measured by immunohistochemistry, Western-blotting and quantitative PCR. STIM1 knockout-HCC cells were generated by CRISPR-Cas9, and gene-overexpression was mediated lentivirus transfection. Besides, the invasive and metastatic activities of HCC cells were assessed by transwell assay, anoikis rate and lung metastasis . Seahorse energy analysis and micro-array were used to evaluate the glucose and lipid metabolism. : STIM1 was down-regulated in metastatic HCC cells rather than in proliferating HCC cells, and low STIM1 levels were associated with poor outcome of HCC patients. During tumor growth, STIM1 stabilized Snail1 protein by activating the CaMKII/AKT/GSK-3β pathway. Subsequently, the upregulated Snail1 suppressed STIM1/SOCE during metastasis. STIM1 restoration significantly diminished anoikis-resistance and metastasis induced by Snail1. Mechanistically, the downregulated STIM1 shifted the anabolic/catabolic balance, , from aerobic glycolysis towards AMPK-activated fatty acid oxidation (FAO), which contributed to Snail1-driven metastasis and anoikis-resistance. : Our data provide the molecular basis that STIM1 orchestrates invasion and metastasis reprogramming HCC metabolism.
: 发生侵袭和转移的癌细胞表现出糖酵解减弱但脂肪酸氧化（FAO）增强的表型。钙（Ca）介导的信号通路与肿瘤转移和代谢调节有关。基质相互作用分子 1（STIM1）触发的储存操纵 Ca 内流（SOCE）是包括肝细胞癌（HCC）细胞在内的非兴奋细胞 Ca 内流的主要途径。然而，STIM1 是否以及如何调节 HCC 的侵袭和转移代谢重编程尚不清楚。 : 通过免疫组织化学、Western-blotting 和定量 PCR 测量 HCC 组织和细胞中 STIM1 和 Snail1 的表达。通过 CRISPR-Cas9 生成 STIM1 敲除 HCC 细胞，并通过慢病毒转染介导基因过表达。此外，通过 Transwell 测定、贴壁凋亡率和肺转移评估 HCC 细胞的侵袭和转移活性。使用 Seahorse 能量分析和微阵列评估葡萄糖和脂质代谢。 : STIM1 在转移性 HCC 细胞中下调，而在增殖性 HCC 细胞中上调，低 STIM1 水平与 HCC 患者的不良预后相关。在肿瘤生长过程中，STIM1 通过激活 CaMKII/AKT/GSK-3β 通路稳定 Snail1 蛋白。随后，上调的 Snail1 在转移过程中抑制 STIM1/SOCE。STIM1 恢复显著降低了 Snail1 诱导的贴壁凋亡抵抗和转移。在机制上，下调的 STIM1 改变了合成代谢/分解代谢平衡，从有氧糖酵解转向 AMPK 激活的脂肪酸氧化（FAO），这有助于 Snail1 驱动的转移和贴壁凋亡抵抗。 : 我们的数据提供了 STIM1 协调侵袭和转移的分子基础，重编程 HCC 代谢。
