Theranostics 2020; 10(14):6483-6499. doi:10.7150/thno.44025

Research Paper

STIM1 is a metabolic checkpoint regulating the invasion and metastasis of hepatocellular carcinoma

Huakan Zhao1,2,*, Guifang Yan2,*, Lu Zheng3,*, Yu Zhou1,2, Halei Sheng1, Lei Wu1,2, Qi Zhang1,2, Juan Lei1,2, Jiangang Zhang1,2, Rong Xin1, Lu Jiang1, Xiao Zhang1,2, Yu Chen1,2, Jingchun Wang1, Yanquan Xu1, Dingshan Li1, Yongsheng Li1,2✉

1. Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
2. Institute of Cancer, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
3. Department of Hepatobiliary Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Zhao H, Yan G, Zheng L, Zhou Y, Sheng H, Wu L, Zhang Q, Lei J, Zhang J, Xin R, Jiang L, Zhang X, Chen Y, Wang J, Xu Y, Li D, Li Y. STIM1 is a metabolic checkpoint regulating the invasion and metastasis of hepatocellular carcinoma. Theranostics 2020; 10(14):6483-6499. doi:10.7150/thno.44025. Available from http://www.thno.org/v10p6483.htm

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Abstract

Background: Cancer cells undergoing invasion and metastasis possess a phenotype with attenuated glycolysis, but enhanced fatty acid oxidation (FAO). Calcium (Ca2+)-mediated signaling pathways are implicated in tumor metastasis and metabolism regulation. Stromal-interaction molecule 1 (STIM1) triggered store-operated Ca2+ entry (SOCE) is the major route of Ca2+ influx for non-excitable cells including hepatocellular carcinoma (HCC) cells. However, whether and how STIM1 regulates the invasion and metastasis of HCC via metabolic reprogramming is unclear.

Methods: 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 via lentivirus transfection. Besides, the invasive and metastatic activities of HCC cells were assessed by transwell assay, anoikis rate in vitro and lung metastasis in vivo. Seahorse energy analysis and micro-array were used to evaluate the glucose and lipid metabolism.

Results: 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, i.e., from aerobic glycolysis towards AMPK-activated fatty acid oxidation (FAO), which contributed to Snail1-driven metastasis and anoikis-resistance.

Conclusions: Our data provide the molecular basis that STIM1 orchestrates invasion and metastasis via reprogramming HCC metabolism.

Keywords: invasion and metastasis, metabolic reprogramming, Snail1, SOCE, STIM1