High hepatic expression of PDK4 improves survival upon multimodal treatment of colorectal liver metastases
High hepatic expression of PDK4 improves survival upon multimodal treatment of colorectal liver metastases
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DOI：
10.1038/s41416-019-0406-9
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发表时间：
2019-04-02
影响因子：
8.8
通讯作者：
Schneider, Martin
中科院分区：
文献类型：
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作者：
Strowitzki, Moritz J.;Radhakrishnan, Praveen;Schneider, Martin
背景技术背景：交界性可切除的结直肠肝转移（CRLM）患者经常接受新辅助化疗（NC）以减轻肿瘤负荷，从而使手术切除可行。尽管NC可以诱导严重的肝损伤，但大多数研究基于组织的预后标志物的研究都集中在肿瘤组织上。在这里，我们评估的预后意义的磷酸脱氢酶激酶同工酶4（PDK4）的患者接受手术切除，由于CRLM。方法：缺氧适应基因（如PDK同工酶）的转录水平进行了评估，在健康的肝脏，相应的CRLM，健康的结肠粘膜和相应的肿瘤组织。进行单因素和多因素分析。对化疗后的PDK4上调或下调的反应进行了研究，在vitro.RESULTS：PDK4在健康肝组织内的表达与CRLM手术切除后的总生存率和肝功能增加相关。这种关联在NC患者中增强。CRLM组织中的PDK4表达与总生存期无关。PDK4的上调增加了肝细胞和结肠癌细胞对化疗诱导的毒性的抵抗力，而PDK4的敲低增强了化疗相关的细胞damage.CONCLUSION：我们的研究结果表明，上调PDK4的表达降低了肝脏化疗诱导的氧化应激，并与改善术后肝功能的患者进行多模式治疗和切除CRLM。
BACKGROUND: Patients with borderline resectable colorectal liver metastases (CRLM) frequently receive neoadjuvant chemotherapy (NC) to reduce tumour burden, thus making surgical resection feasible. Even though NC can induce severe liver injury, most studies investigating tissue-based prognostic markers focus on tumour tissue. Here, we assessed the prognostic significance of pyruvate-dehydrogenase-kinase isoenzyme 4 (PDK4) within liver tissue of patients undergoing surgical resection due to CRLM.METHODS: Transcript levels of hypoxia-adaptive genes (such as PDK isoenzymes) were assessed in the tissue of healthy liver, corresponding CRLM, healthy colon mucosa and corresponding tumour. Uni- and multivariate analyses were performed. Responses to chemotherapy upon up- or down-regulation of PDK4 were studied in vitro.RESULTS: PDK4 expression within healthy liver tissue was associated with increased overall survival and liver function following surgical resection of CRLM. This association was enhanced in patients with NC. PDK4 expression in CRLM tissue did not correlate with overall survival. Up-regulation of PDK4 increased the resistance of hepatocytes and colon cancer cells against chemotherapy-induced toxicity, whereas knockdown of PDK4 enhanced chemotherapy-associated cell damage.CONCLUSION: Our findings suggest that up-regulated PDK4 expression reduces hepatic chemotherapy-induced oxidative stress and is associated with improved postoperative liver function in patients undergoing multimodal treatment and resection of CRLM.