PARP9-PARP13-PARP14 axis tunes colorectal cancer response to radiotherapy.

IF 12.8 1区 医学 Q1 ONCOLOGY
Rimvile Prokarenkaite, Karolina Kuodyte, Greta Gudoityte, Elzbieta Budginaite, Daniel Naumovas, Egle Strainiene, Kristijonas Velickevicius, Audrius Dulskas, Ernestas Sileika, Jonas Venius, Virginijus Tunaitis, Augustas Pivoriunas, Vytaute Starkuviene, Vaidotas Stankevicius, Kestutis Suziedelis
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引用次数: 0

Abstract

Background: Colorectal cancer (CRC) is the third most prevalent cancer worldwide. Despite substantial advancements in CRC therapy in recent years, ionizing radiation (IR) continues to be the predominant treatment for colon malignances. However, it still lacks the precision required for excellent therapeutic outcomes, ultimately resulting in tumor radioresistance. This study seeks to explore the potential of atypical PARPs including PARP9, PARP12, PARP13 and PARP14 as innovative radiosensitizing targets for CRC.

Methods: We utilized CRISPR/Cas9-mediated gene editing to knockout the PARP9, PARP12, PARP13 and PARP14 in HT29 and DLD1 cells. The cells were exposed to either a single dose of 6-10 Gy or to fractionated dose of 5 × 2 Gy X-ray radiation cultivating cells in 2D, laminin-rich ECM 3D and multicellular spheroid models. The transcriptomes of nonirradiated and irradiated cells were analyzed using microarrays. Gene set enrichment analysis was conducted to determine the pathways in which PARP13 is engaged. Cell viability was assessed using a clonogenic assay. Gene expression levels in cells and patient samples were quantified using RT-qPCR.

Results: The expression of PARP9, PARP12, PARP13 and PARP14 was particularly elevated in irradiated colorectal cancer HT29 cells in a microenvironment-dependent manner. PARP13 deficiency significantly enhanced the sensitivity of HT29 cells to both single-dose and multifractionated irradiation regimens, resulting in reduced colony formation and spheroidal integrity. Microarray analysis indicated that PARP13 may modulate the expression genes associated with immune response signaling pathways, including members of PARP family. Furthermore, PARP13 loss in HT29 cells markedly impaired the expression of immune response related genes following multifractionated ionizing irradiation. Finally, chemoradiotherapy significantly elevated the expression of PARP9, PARP12, PARP13 and PARP14 in rectal tumors, while having no effect on adjacent normal colon tissues. Elevated pre-treatment PARP9 expression levels and a blunted post-treatment increase in PARP9 and PARP14 expression predicted poor overall survival in rectal cancer patients, while PARP13 emerged as the most significant discriminator between tumor and healthy tissue.

Conclusions: Collectively, the PARP9/13/14 axis is implicated in the response of CRC to radiation treatment in both preclinical and clinical settings, demonstrating the atypical members of the PARP family as attractive targets for neoadjuvant radiotherapy.

PARP9-PARP13-PARP14轴调节结直肠癌对放疗的反应。
背景:结直肠癌(CRC)是全球第三大流行癌症。尽管近年来CRC治疗取得了实质性进展,但电离辐射(IR)仍然是结肠恶性肿瘤的主要治疗方法。然而,它仍然缺乏良好治疗效果所需的精度,最终导致肿瘤放射耐药。本研究旨在探索包括PARP9、PARP12、PARP13和PARP14在内的非典型parp作为CRC创新放射增敏靶点的潜力。方法:利用CRISPR/ cas9介导的基因编辑技术敲除HT29和DLD1细胞中的PARP9、PARP12、PARP13和PARP14。将细胞暴露于单剂量6-10 Gy或5 × 2 Gy的x射线辐射中,培养2D、富含层粘胶蛋白的ECM 3D和多细胞球体模型的细胞。使用微阵列分析未辐照和辐照细胞的转录组。进行基因集富集分析以确定PARP13参与的途径。细胞活力用克隆测定法评估。采用RT-qPCR定量检测细胞和患者样本中的基因表达水平。结果:PARP9、PARP12、PARP13和PARP14的表达在辐照后的结直肠癌HT29细胞中以微环境依赖的方式显著升高。PARP13缺乏显著增强了HT29细胞对单次和多次辐照方案的敏感性,导致集落形成和球体完整性减少。微阵列分析表明,PARP13可能调节免疫应答信号通路相关基因的表达,包括PARP家族成员。此外,在HT29细胞中,PARP13的缺失显著损害了多重电离辐照后免疫应答相关基因的表达。最后,放化疗显著提高了直肠肿瘤中PARP9、PARP12、PARP13和PARP14的表达,而对邻近正常结肠组织无影响。治疗前PARP9表达水平升高,治疗后PARP9和PARP14表达增加减弱,预示着直肠癌患者的总生存率较低,而PARP13成为肿瘤与健康组织之间最显著的鉴别因子。结论:总的来说,PARP9/13/14轴在临床前和临床环境中都与结直肠癌对放射治疗的反应有关,表明PARP家族的非典型成员是新辅助放疗的有吸引力的靶点。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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