三萜类熊果酸调节环境致癌物苯并[a]芘驱动的 SKH-1 无毛小鼠表观遗传和代谢改变,以阻断皮肤癌的发生。

IF 3.3 3区 医学 Q2 ONCOLOGY
Md Shahid Sarwar, Christina N Ramirez, Hsiao-Chen Dina Kuo, Pochung Chou, Renyi Wu, Davit Sargsyan, Yuqing Yang, Ahmad Shannar, Rebecca Mary Peter, Ran Yin, Yujue Wang, Xiaoyang Su, Ah-Ng Kong
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引用次数: 0

摘要

多环芳烃(PAHs)是无处不在的环境致癌物质,可导致皮肤癌的发生。最近,我们报道了暴露于常见多环芳烃苯并[a]芘(B[a]P)会导致非黑色素瘤皮肤癌(NMSC)的诱发、促进和进展过程中的表观遗传和代谢改变。作为一项后续调查,本研究探讨了三萜类熊果酸如何调节 SKH-1 无毛小鼠体内 B[a]P 驱动的表观遗传和代谢途径。我们的研究结果表明,熊果酸能在非小细胞肺癌的不同阶段抑制 B[a]P 诱导的肿瘤发生。表观基因组 CpG 甲基序列数据显示,UA 可减少 B[a]P 介导的差异甲基化区域(DMRs)。转录组RNA-seq显示,UA抑制了富亮氨酸重复LGI家族成员2(Lgi2)和胰激肽原相关肽酶13(Klk13)等B[a]P诱导的皮肤癌相关基因的差异表达基因(DEGs),表明UA在B[a]P介导的基因调控中发挥着重要作用,并在NMSC阻断过程中产生了潜在影响。对DEGs和DMRs的关联分析发现,在早期对比组中,KLK13基因的mRNA表达与启动子CpG甲基化状态相关,表明UA可在NMSC早期通过调节KLK13启动子甲基化来调控KLK13。代谢组学研究显示,UA改变了B[a]P调控的癌症相关代谢,如启动期的硫胺素代谢、抗坏血酸和醛二酸代谢;促进期的丙酮酸、柠檬酸和硫胺素代谢;以及晚期的β-丙氨酸和Pathothenate CoA生物合成。综上所述,UA 可逆转 B[a]P 驱动的表观遗传学、转录组和代谢重编程,可能有助于全面阻断 B[a]P 介导的 NMSC。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Triterpenoid ursolic acid regulates the environmental carcinogen benzo[a]pyrene-driven epigenetic and metabolic alterations in SKH-1 hairless mice for skin cancer interception.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens accountable to developing skin cancers. Recently, we reported that exposure to benzo[a]pyrene (B[a]P), a common PAH, causes epigenetic and metabolic alterations in the initiation, promotion and progression of non-melanoma skin cancer (NMSC). As a follow-up investigation, this study examines how dietary triterpenoid ursolic acid (UA) regulates B[a]P-driven epigenetic and metabolic pathways in SKH-1 hairless mice. Our results show UA intercepts against B[a]P-induced tumorigenesis at different stages of NMSC. Epigenomic cytosines followed by guanine residues (CpG) methyl-seq data showed UA diminished B[a]P-mediated differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq revealed UA revoked B[a]P-induced differentially expressed genes (DEGs) of skin cancer-related genes, such as leucine-rich repeat LGI family member 2 (Lgi2) and kallikrein-related peptidase 13 (Klk13), indicating UA plays a vital role in B[a]P-mediated gene regulation and its potential consequences in NMSC interception. Association analysis of DEGs and DMRs found that the mRNA expression of KLK13 gene was correlated with the promoter CpG methylation status in the early-stage comparison group, indicating UA could regulate the KLK13 by modulating its promoter methylation at an early stage of NMSC. The metabolomic study showed UA alters B[a]P-regulated cancer-associated metabolisms like thiamin metabolism, ascorbate and aldarate metabolism during the initiation phase; pyruvate, citrate and thiamin metabolism during the promotion phase; and beta-alanine and pathothenate coenzyme A (CoA) biosynthesis during the late progression phase. Taken together, UA reverses B[a]P-driven epigenetic, transcriptomic and metabolic reprogramming, potentially contributing to the overall cancer interception against B[a]P-mediated NMSC.

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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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