PO.MCB11.01 · 分子与细胞生物学
探究NISCH在乳腺癌中的抑癌功能及调控机制
Investigating tumor suppressor function and regulatory control of NISCH in breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：本研究旨在通过检验Nischarin（NISCH）的表达模式与临床结局的关系，并探索可能导致其失调的潜在调控机制——特别是启动子甲基化和拷贝数改变——来表征NISCH在乳腺癌中的作用。
方法：通过UCSC Xena和cBioPortal从乳腺癌国际联盟分子分类学（METABRIC）和癌症基因组图谱（TCGA）获取NISCH的数据，包括NISCH和几种DNA甲基转移酶（DNMT）的表达水平、启动子甲基化beta值、拷贝数值、人口学变量和临床数据。所有回顾性分析均使用GraphPad Prism进行。
结果：NISCH的高表达与乳腺癌总生存期改善显著相关，同时也与更长的无远处转移生存期和无复发生存期相关。在比较人口学特征时，在较年轻确诊的患者、Basal PAM-50亚型内以及亚裔人群中观察到较低的NISCH表达。启动子区域邻近的几个CpG岛既与NISCH表达呈负相关，又在肿瘤样本中甲基化升高。共表达研究揭示了三种DNMT与NISCH之间的负相关，提示其可能参与该基因的沉默。此外，NISCH位点的浅缺失与mRNA表达降低相关，并与较差的生存结局相关联。
结论：综上，这些发现支持NISCH作为乳腺癌抑癌基因的特征，其高mRNA表达在多个临床指标上始终与更好的生存结局相关。此外，在生物学上更具侵袭性的乳腺癌亚群——Basal PAM-50亚型和较年轻确诊年龄——中鉴定出较低的NISCH表达，增强了NISCH作为不良预后推定标志物的地位。启动子甲基化和浅缺失均降低了NISCH的表达，表明该位点可能通过多种基因组和表观遗传机制受到调控。NISCH与三种DNMT在相似人口学亚群中的反向表达模式提供了进一步证据，表明启动子甲基化可能驱动沉默过程。总体而言，这些发现强化了未来开展功能研究以探究控制NISCH表达机制、并评估其作为乳腺癌生物标志物或治疗靶点潜力的理论依据。
查看英文原文 English abstract
Purpose: This study aimed to characterize the role of Nischarin (NISCH) in breast cancer by examining its expression patterns in relation to clinical outcomes and exploring potential regulatory mechanisms-specifically promoter methylation and copy number alterations-that may underlie its dysregulation.
Methods: Data were acquired for NISCH from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) via UCSC Xena and cBioPortal, including expression levels of NISCH and several DNA methyltransferases (DNMTs), promoter methylation beta values, copy-number values, demographic variables, and clinical data. All retrospective analyses were performed using GraphPad Prism.
Results: High expression of NISCH was significantly associated with improved overall survival in breast cancer, as well as longer distant metastasis-free survival and relapse-free survival. When comparing demographics, a lower expression of NISCH was observed in patients diagnosed at younger ages, within the Basal PAM-50 subtype, and among the Asian race. Several CpG islands proximal to the promoter region showed both a negative correlation with NISCH expression and elevated methylation in tumor samples. Co-expression studies revealed inverse correlations between three DNMTs and NISCH, indicating possible involvement in the silencing of the gene. Furthermore, shallow deletions at the NISCH locus correlated with reduced mRNA expression and were linked to poorer survival outcomes.
Conclusions: Together these findings support NISCH's profile as a tumor suppressor in breast cancer, with high mRNA expression consistently linked to better survival outcomes across multiple clinical metrics. Moreover, identifying lower NISCH expression in biologically aggressive subsets of breast cancer-the Basal PAM-50 subtype and younger age at diagnosis-enhances NISCH as a putative marker for poor prognosis. Both promoter methylation and shallow deletions reduced expression of NISCH, indicating that the locus may be regulated through several genomic and epigenetic mechanisms. Inverse expression patterns between NISCH and three DNMTs across similar demographic subsets provides additional evidence that promoter-methylation may drive the silencing process. Collectively, these findings strengthen the rationale for future functional studies to investigate the mechanisms controlling NISCH expression, and to evaluate its potential as a biomarker or therapeutic target in breast cancer.
利益披露 Disclosure
A. E. Rink, None.