Ryanodine receptor 2 promotes colorectal cancer metastasis by the ROS/BACH1 axis.
Ryanodine receptor 2 promotes colorectal cancer metastasis by the ROS/BACH1 axis.
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Ryanodine受体2通过ROS/BACH1轴促进结直肠癌转移
DOI：
10.1002/1878-0261.13350
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发表时间：
2023-04
影响因子：
6.6
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中科院分区：
文献类型：
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目前尚无针对KRAS原癌基因GT3（KRAS）突变转移性结直肠癌（mCRC）的靶向治疗，因为其潜在机制仍不清楚。基于生物信息学分析，本研究的目的是阐明一个潜在的基因靶点，批准的药物，并揭示候选基因的功能以及潜在的机制。在这里，我们确定了Ryanodine受体2（RyR 2）表达在KRAS突变型mCRC中上调，这促进了癌细胞转移。S107是临床上批准的抑制RyR 2钙释放的药物，在体外和体内均抑制癌细胞转移。RyR 2的高表达预测我们的患者队列的生存率低。有浆膜浸润和血管癌栓的CRC患者的特征是RyR 2高表达。RyR 2敲低和抑制后的表达谱分析揭示了一组转移相关分子，并将BTB结构域和CNC同源物1（BACH 1）鉴定为受RyR 2调节的主要转录因子。RyR 2调节细胞活性氧（ROS）水平，从而激活核因子红细胞2相关因子2（Nrf 2;也称为NFE 2L 2）和HMOX 1表达，从而促进BACH 1积累。总的来说，这项研究提供的证据表明，RyR 2/ROS/BACH 1轴可能是CRC转移的潜在干预靶点。通过生物信息学分析结合分子策略，确定RyR 2是大肠癌转移的调节因子。RyR 2的表达提高了细胞内Ca 2+浓度，促进了细胞内ROS水平，这反过来又激活了Nrf 2活性，随后是BACH 1积累。BACH 1积累导致癌细胞转移进展的启动。
There is no targeted therapy for KRAS proto‐oncogene, GTPase (KRAS)‐mutant metastatic colorectal cancer (mCRC) because the underlying mechanism remains obscure. Based on bioinformatic analysis, this study aims to elucidate a potential gene target for which an approved drug is available, and to reveal the function as well as the underlying mechanism of the candidate gene. Here, we identified that ryanodine receptor 2 (RyR2) expression was upregulated in KRAS‐mutant mCRC, and that this promoted cancer cell metastasis. S107, an approved drug to inhibit calcium release from RyR2 in the clinic, inhibited cancer cell metastasis both in vitro and in vivo. High expression of RyR2 predicts poor survival in our patient cohort. CRC patients with serosa invasion and vascular tumor thrombus are characterized by high RyR2 expression. Analysis of expression profiles upon RyR2 knockdown and inhibition, revealed a set of metastasis‐related molecules, and identified BTB domain and CNC homolog 1 (BACH1) as the main transcription factor regulated by RyR2. RyR2 regulates cellular reactive oxygen species (ROS) levels, which activates nuclear factor erythroid 2‐related factor 2 (Nrf2; also known as NFE2L2) and HMOX1 expression, and thus BACH1 accumulation. Collectively, this study provides evidence that the RyR2/ROS/BACH1 axis may be a potential intervention target for CRC metastasis. Through bioinformatics analysis combined with molecular strategies, RyR2 was identified as a regulator of colorectal cancer metastasis. RyR2 expression raised intracellular Ca2+ concentration and promoted cellular ROS levels, which in turn activated Nrf2 activity followed by BACH1 accumulation. The BACH1 accumulation led to the start‐up of the metastasis progression of cancer cells.