Down-regulation of ALDOB during metabolic reprogramming mediates malignant behavior in hepatocellular carcinoma and insensitivity to postoperative adjuvant transarterial chemoembolization
Down-regulation of ALDOB during metabolic reprogramming mediates malignant behavior in hepatocellular carcinoma and insensitivity to postoperative adjuvant transarterial chemoembolization
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DOI：
10.1042/cs20220661
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发表时间：
2023-02-01
期刊：
影响因子：
6
通讯作者：
Qi，Lu-Nan
中科院分区：
文献类型：
--
作者：
Xu，Jing-Xuan;Qin，Shui-Lin;Qi，Lu-Nan
背景：术后经动脉化疗栓塞（PA-TACE）是预防肝细胞癌（HCC）术后早期复发的有效辅助治疗方法。然而，许多患者对此并不敏感。因此，本研究旨在探讨PA-TACE耐药的深层次原因，为选择从PA-TACE中获益最大的患者提供可靠依据。 方法：利用微阵列数据分析PA-TACE敏感或不敏感患者原发肿瘤的独特基因表达谱。结合差异表达分析、基因集富集分析 (GSEA) 和加权相关网络分析 (WGCNA) 来筛选 PA-TACE 不敏感的潜在驱动因素。肝癌细胞系中ALDOB表达沉默或过表达，在常氧和缺氧条件下观察到糖酵解活性、周期、凋亡和恶性生物学表型的变化。最后构建动物模型验证ALDOB失调对HCC细胞体内致瘤能力的影响。结果：抑制ALDOB促进Ki67表达上调，糖酵解活性显着增强。此外，HCC细胞的增殖、侵袭和迁移能力增强，在缺氧情况下更严重。恶性行为的这一优势也得到了体内模型的验证。结论：ALDOB 的下调可能是在 HCC 中观察到的代谢重编程的基础，通过促进 HCC 细胞的恶性行为。缺氧和ALDOB下调具有相加作用，与PA-TACE不敏感密切相关。使用 ALDOB 和 Ki67 作为组合标记有可能识别“PA-TACE 受益人群”。
Background:Postoperative transarterial chemoembolization (PA-TACE) is an effective adjuvant therapy for preventing early postoperative recurrence of hepatocellular carcinoma (HCC); however, many patients are insensitive to it. Therefore, the present study aimed to explore the in-depth reasons for PA-TACE resistance and provide a reliable basis for selecting patients who will benefit the most from PA-TACE.Methods:The unique gene expression profiles of primary tumors from PA-TACE-sensitive or -insensitive patients were analyzed using microarray data. Combined differential expression analysis, gene set enrichment analysis (GSEA), and weighted correlation network analysis (WGCNA) were used to screen for potential drivers of PA-TACE insensitivity. The expression ofALDOBwas silenced or overexpressed in hepatoma cell lines, and changes in glycolytic activity, cycle, apoptosis, and malignant biological phenotypes were observed under normoxia and hypoxia. Finally, an animal model was constructed to verify the effects ofALDOBdysregulation on the tumorigenic ability of HCC cellsin vivo.Results:The inhibition ofALDOBpromoted the up-regulation ofKi67expression, and glycolytic activity was significantly enhanced. Moreover, the proliferation, invasion, and migration capabilities were increased in HCC cells and even worse in hypoxia. This advantage of malignant behavior was also validated usingin vivomodels.Conclusion:Down-regulation ofALDOBmay underlie the metabolic reprogramming observed in HCC by promoting the malignant behavior of HCC cells. Hypoxia andALDOBdown-regulation acted additively, which was closely related to PA-TACE insensitivity. The use ofALDOBandKi67as a combined marker has the potential to identify the ‘PA-TACE beneficiary population’.