Upregulation of Apoptosis Related Genes in Clinically Normal Tongue Contralateral to Squamous Cell Carcinoma of the Oral Tongue, an Effort to Maintain Tissue Homeostasis.

IF 3.2 Q2 PATHOLOGY

Head & Neck Pathology Pub Date : 2024-09-30 DOI:10.1007/s12105-024-01695-6

Nima Attaran, Philip J Coates, Katarina Zborayova, Nicola Sgaramella, Karin Nylander, Xiaolian Gu

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引用次数: 0

Abstract

Purpose: The field cancerization concept indicates the presence of pre-cancerous changes in clinically normal tissue surrounding the tumor. In squamous cell carcinoma of the oral tongue (SCCOT) which is infrequently linked to human papillomavirus infection, we have previously reported that clinically normal tongue contralateral to tumor (NTCT) is molecularly abnormal. Here, combining our transcriptomic and genomic data, we aimed to investigate the contribution of molecular changes in NTCT to cancer development.

Methods: Microarray gene expression data of 14 healthy controls, 23 NTCT and 29 SCCOT samples were investigated to characterize transcriptional profiles in NTCT. Whole exome sequencing and RNA-sequencing data of paired NTCT and tumor samples from 15 SCCOT patients were used to study correlation between copy number variation and differential gene expression.

Results: Using supervised multivariate partial least squares discriminant analysis, a total of 61 mRNAs that distinguish NTCT from healthy tongue were selected. Functional enrichment analysis of the 22 upregulated genes showed increased "positive regulation of nitrogen compound metabolic process" in NTCT. All 12 genes involved in this process have roles in apoptosis (anti- and/or pro-apoptotic). Compared to healthy controls, Zinc Finger Protein 395 (ZNF395), a pro-apoptotic tumor suppressor located on chromosome 8p, was the only gene showing increased mRNA level in NTCT whereas decreased in SCCOT. Given the frequent loss of chromosome 8p in SCCOT, the impact of ZNF395 copy number variation on gene expression was further examined, revealing a positive correlation between copy number and mRNA level (correlation coefficient = 0.572, p < 0.001).

Conclusion: NTCT is susceptible to malignant transformation, where tissue homeostasis is maintained at least partly through regulation of apoptosis. Loss of the pro-apoptotic gene ZNF395 could thus initiate cancer development.

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临床正常舌与口腔舌鳞状细胞癌对侧凋亡相关基因的上调是维持组织稳态的一种努力。

目的：现场癌化概念是指肿瘤周围的临床正常组织出现癌前病变。口腔舌鳞状细胞癌（SCCOT）很少与人类乳头瘤病毒感染有关，我们以前曾报道过肿瘤对侧的临床正常舌（NTCT）存在分子异常。在此，我们结合转录组和基因组数据，旨在研究 NTCT 分子变化对癌症发展的贡献：方法：研究了14个健康对照组、23个NTCT样本和29个SCCOT样本的微阵列基因表达数据，以确定NTCT的转录特征。利用15例SCCOT患者的NTCT和肿瘤配对样本的全外显子组测序和RNA测序数据，研究拷贝数变异与不同基因表达之间的相关性：结果：通过有监督的多元偏最小二乘法判别分析，共筛选出61个能区分NTCT和健康舌的mRNA。对 22 个上调基因的功能富集分析表明，NTCT 中 "氮化合物代谢过程的正调控 "增加。参与这一过程的所有 12 个基因都在细胞凋亡（抗凋亡和/或促凋亡）中发挥作用。与健康对照组相比，锌指蛋白 395（ZNF395）是唯一一个在 NTCT 中 mRNA 水平升高而在 SCCOT 中降低的基因，锌指蛋白 395 是一种位于 8p 染色体上的促凋亡肿瘤抑制因子。鉴于 SCCOT 中 8p 染色体的频繁缺失，研究人员进一步研究了 ZNF395 拷贝数变化对基因表达的影响，结果显示拷贝数与 mRNA 水平呈正相关（相关系数 = 0.572，p 结论：ZNF395 拷贝数的变化对基因表达的影响是不确定的：NTCT 易发生恶性转化，其组织稳态至少部分是通过调节细胞凋亡来维持的。因此，促凋亡基因 ZNF395 的缺失可能导致癌症的发生。

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

Head & Neck Pathology PATHOLOGY-

CiteScore

5.70

自引率

9.50%

发文量

期刊介绍： Head & Neck Pathology presents scholarly papers, reviews and symposia that cover the spectrum of human surgical pathology within the anatomic zones of the oral cavity, sinonasal tract, larynx, hypopharynx, salivary gland, ear and temporal bone, and neck. The journal publishes rapid developments in new diagnostic criteria, intraoperative consultation, immunohistochemical studies, molecular techniques, genetic analyses, diagnostic aids, experimental pathology, cytology, radiographic imaging, and application of uniform terminology to allow practitioners to continue to maintain and expand their knowledge in the subspecialty of head and neck pathology. Coverage of practical application to daily clinical practice is supported with proceedings and symposia from international societies and academies devoted to this field. Single-blind peer review The journal follows a single-blind review procedure, where the reviewers are aware of the names and affiliations of the authors, but the reviewer reports provided to authors are anonymous. Single-blind peer review is the traditional model of peer review that many reviewers are comfortable with, and it facilitates a dispassionate critique of a manuscript.