Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.
III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
J Exp Clin Cancer Res. 2024 Apr 11;43(1):110. doi: 10.1186/s13046-024-03020-z.
Metastasis is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC) patients. We previously showed that low HERC5 expression predicts early tumor dissemination and a dismal prognosis in NSCLC patients. Here, we performed functional studies to unravel the mechanism underlying the "metastasis-suppressor" effect of HERC5, with a focus on mitochondrial metabolism pathways.
We assessed cell proliferation, colony formation potential, anchorage-independent growth, migration, and wound healing in NSCLC cell line models with HERC5 overexpression (OE) or knockout (KO). To study early tumor cell dissemination, we used these cell line models in zebrafish experiments and performed intracardial injections in nude mice. Mass spectrometry (MS) was used to analyze protein changes in whole-cell extracts. Furthermore, electron microscopy (EM) imaging, cellular respiration, glycolytic activity, and lactate production were used to investigate the relationships with mitochondrial energy metabolism pathways.
Using different in vitro NSCLC cell line models, we showed that NSCLC cells with low HERC5 expression had increased malignant and invasive properties. Furthermore, two different in vivo models in zebrafish and a xenograft mouse model showed increased dissemination and metastasis formation (in particular in the brain). Functional enrichment clustering of MS data revealed an increase in mitochondrial proteins in vitro when HERC5 levels were high. Loss of HERC5 leads to an increased Warburg effect, leading to improved adaptation and survival under prolonged inhibition of oxidative phosphorylation.
Taken together, these results indicate that low HERC5 expression increases the metastatic potential of NSCLC in vitro and in vivo. Furthermore, HERC5-induced proteomic changes influence mitochondrial pathways, ultimately leading to alterations in energy metabolism and demonstrating its role as a new potential metastasis suppressor gene.
转移是非小细胞肺癌（NSCLC）患者癌症相关死亡的主要原因。我们之前表明，HERC5 低表达可预测 NSCLC 患者的早期肿瘤扩散和预后不良。在这里，我们进行了功能研究，以揭示 HERC5“抑制转移”作用的机制，重点是线粒体代谢途径。
我们评估了 HERC5 过表达（OE）或敲除（KO）的 NSCLC 细胞系模型中的细胞增殖、集落形成潜力、无锚定生长、迁移和伤口愈合。为了研究早期肿瘤细胞扩散，我们在斑马鱼实验中使用这些细胞系模型，并在裸鼠中进行心内注射。质谱（MS）用于分析全细胞提取物中的蛋白质变化。此外，电子显微镜（EM）成像、细胞呼吸、糖酵解活性和乳酸产生用于研究与线粒体能量代谢途径的关系。
使用不同的 NSCLC 细胞系模型，我们表明 HERC5 低表达的 NSCLC 细胞具有增加的恶性和侵袭特性。此外，在斑马鱼和异种移植小鼠模型中的两种不同的体内模型中，观察到扩散和转移形成增加（特别是在大脑中）。MS 数据的功能富集聚类显示，HERC5 水平高时体外线粒体蛋白增加。HERC5 缺失会导致瓦博格效应增加，导致在氧化磷酸化长期抑制下适应性和生存能力提高。
总之，这些结果表明，HERC5 低表达会增加 NSCLC 在体外和体内的转移潜力。此外，HERC5 诱导的蛋白质组变化影响线粒体途径，最终导致能量代谢的改变，并证明其作为新的潜在转移抑制基因的作用。
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