High expression of PAX8-AS1 correlates with poor prognosis and response to fluorouracil-based chemotherapy in stage II colon cancer

IF 5 2区医学 Q2 Medicine

Translational Oncology Pub Date : 2024-09-19 DOI:10.1016/j.tranon.2024.102128

Hongsheng Fang , Lingyu Han , Yun Xu , Ruiqi Gu , Guoxiang Cai , Zuguang Xia , Weixing Dai , Renjie Wang

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引用次数: 0

Abstract

Decisions regarding adjuvant therapy in patients with stage II colon cancer remains controversial and challenging. We aimed to determine novel biomarkers that help to predict relapse free survival (RFS) and identify a subset of patients with stage II colon cancer who could gain survival benefits from adjuvant chemotherapy. Public microarray datasets of stage II colon cancer samples were extracted from Gene Expression Omnibus database. Global gene expression changes were then analyzed between the paired early relapse and long-term survival group to identify the differentially expressed mRNAs and lncRNAs. Based on Lasso Cox regression modeling analysis, a total of 30 mRNAs and 2 lncRNAs were finally identified. With specific formula, stage II patients in training and validation sets were divided into low and risk groups with significantly different RFS. PAX8-AS1 is the novel lncRNA which showed the highest upregulation in early relapse group. Patients with high PAX8-AS1 expression level showed notably poorer RFS in both meta GEO cohort (P = 0.04, Figure 4B) and FUSCC cohort (P < 0.001, Figure 4C). Among the stage II patients with high PAX8-AS1 level, administration of fluorouracil-based adjuvant chemotherapy provided a substantial improvement in RFS (P = 0.002, Figure 3C). Further mechanistic study unveiled that PAX8-AS1 increases the response of CRC cells to chemotherapy in vitro and in vivo by maintaining the mRNA stability of PAX8. In conclusion, PAX8-AS1 as a novel and reliable biomarker for predicting prognosis and identification of patients with stage II disease who could gain survival benefit from fluorouracil-based adjuvant chemotherapy.

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PAX8-AS1 的高表达与 II 期结肠癌的不良预后和对氟尿嘧啶化疗的反应有关

有关 II 期结肠癌患者辅助治疗的决策仍存在争议，且极具挑战性。我们的目的是确定有助于预测无复发生存期（RFS）的新型生物标志物，并确定可从辅助化疗中获益的II期结肠癌患者亚群。研究人员从基因表达总库（Gene Expression Omnibus）数据库中提取了II期结肠癌样本的公开芯片数据集。然后分析配对的早期复发组和长期生存组之间的全局基因表达变化，以确定差异表达的mRNA和lncRNA。根据Lasso Cox回归模型分析，最终确定了30个mRNA和2个lncRNA。通过特定公式，训练集和验证集中的 II 期患者被分为低危和高危组，两组患者的 RFS 有显著差异。PAX8-AS1是新发现的lncRNA，在早期复发组的上调率最高。在meta GEO队列（P = 0.04，图4B）和FUSCC队列（P < 0.001，图4C）中，PAX8-AS1表达水平高的患者RFS明显较差。在PAX8-AS1水平较高的II期患者中，氟尿嘧啶辅助化疗可显著改善RFS（P = 0.002，图3C）。进一步的机理研究发现，PAX8-AS1通过维持PAX8的mRNA稳定性，提高了CRC细胞在体外和体内对化疗的反应。总之，PAX8-AS1是一种新的可靠的生物标记物，可用于预测预后和识别可从氟尿嘧啶辅助化疗中获益的II期患者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Oncology ONCOLOGY-

CiteScore

8.40

自引率

2.00%

发文量

314

审稿时长

54 days

期刊介绍： Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.