Daniela Moreira Mombach, Rafael Luiz Vieira Mercuri, Tiago Minuzzi Freire da Fontoura Gomes, Pedro A F Galante, Elgion Lucio Silva Loreto
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引用次数: 0
摘要
顺铂被广泛用于癌症治疗;因此,了解这种药物的耐药性对治疗实践至关重要。虽然有研究深入探讨了顺铂耐药性背景下的差异基因表达,但发现仍然很少。我们对两种顺铂处理过的卵巢癌细胞系中的转座元件(Transposable Elements, TEs)表达及其对宿主基因的影响进行了全面调查。我们利用 RNA-seq、ATAC-seq 和深入的生物信息学分析比较了顺铂敏感和耐药卵巢癌细胞系。我们的研究结果表明,顺铂疗法不仅改变了顺铂敏感和耐药细胞系中蛋白编码基因的表达,还改变了包括LINE1、Alu和内源性逆转录病毒在内的关键TEs的表达。通过与下游基因共同表达或在插入位点与宿主基因产生嵌合转录本,这些TE似乎能控制蛋白编码基因(包括肿瘤相关基因)的表达。我们的模型发现了影响癌症基因和癌症通路表达的毒性教育因子。总之,我们的研究结果表明,与顺铂治疗相关的TEs改变会协同作用于关键癌基因和细胞通路。这项研究强调了考虑基因组中所有转录元件,尤其是 TE 表达的重要性,有助于全面了解癌症对治疗的反应等复杂模型。
Transposable elements alter gene expression and may impact response to cisplatin therapy in ovarian cancer.
Cisplatin is widely employed for cancer treatment; therefore, understanding resistance to this drug is critical for therapeutic practice. While studies have delved into differential gene expression in the context of cisplatin resistance, findings remain somewhat scant. We performed a comprehensive investigation of transposable elements (TEs) expression and their impact in host genes in two cisplatin-treated ovarian cancer cell lines. RNA-seq, ATAC-seq, and in-depth bioinformatics analysis were used to compare cisplatin-sensitive and -resistant ovarian cancer cell lines. Our results reveal that cisplatin therapy alters not only the expression of protein-coding genes, but also key TEs, including LINE1, Alu, and endogenous retroviruses, in both cisplatin-sensitive and -resistant cell lines. By co-expressing with downstream genes or by creating chimeric transcripts with host genes at their insertion sites, these TEs seem to control the expression of protein-coding genes, including tumor-related genes. Our model uncovers TEs influencing the expression of cancer genes and cancer pathways. Collectively, our findings indicate that TE alterations associated with cisplatin treatment occur in critical cancer genes and cellular pathways synergically. This research highlights the importance of considering the entire spectrum of transcribed elements in the genome, especially TE expression, for a complete understanding of complex models like cancer response to treatment.
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).