TIMELESS deficiency sensitizes thyroid cancer to cisplatin treatment via the DNA damage repair pathway

IF 5 2区 医学 Q2 Medicine
Chaoyu Wang , Ping Yuan , Dai Yang , Boke Liu , Juyong Liang
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引用次数: 0

Abstract

Background

The circadian rhythm plays a crucial role in thyroid cancer progression. DNA damage repair (DDR) pathways are closely associated with the sensitivity to cisplatin. However, the role of circadian rhythm genes on cisplatin resistance in thyroid cancer remains undefined.

Methods

Panels of molecular screening were achieved by signaling antibody array. Molecular expressions were established via western blotting and polymerase chain reaction (PCR). Multiple assays (Cell Counting Kit-8, colony formation, Transwell) were used to assess cellular dynamics. The xenograft tumor model was employed for in vivo therapeutic evaluation.

Results

BCPAP and KTC-1 cells were more resistant to cisplatin than other thyroid cancer cell lines, and DDR pathway activation was detected upon cisplatin treatment in BCPAP and KTC-1. The target that affects cisplatin efficacy was screened among circadian rhythm genes, and found that TIMELESS expression was correlated with the sensitivity to cisplatin and malignant signatures of thyroid cancer. TIMELESS knockdown impaired the DDR pathway activation, and significantly enhanced the efficacy of cisplatin treatment in vitro and in vivo.

Conclusions

The newly identified signaling involving circadian rhythm genes and DDR pathways provided mechanistic insights into the cisplatin sensitization strategy in thyroid cancer. Therefore, TIMELESS may be a promising target in thyroid cancer therapeutics.
TIMELESS缺乏症通过DNA损伤修复途径使甲状腺癌对顺铂治疗敏感
昼夜节律在甲状腺癌的进展中起着至关重要的作用。DNA损伤修复(DDR)途径与顺铂敏感性密切相关。然而,昼夜节律基因在甲状腺癌顺铂耐药中的作用尚不明确。方法采用信号抗体阵列技术进行分子筛选。通过western blotting和聚合酶链反应(PCR)建立分子表达。多种检测方法(Cell Counting Kit-8,菌落形成,Transwell)用于评估细胞动力学。采用异种移植瘤模型进行体内治疗评价。结果BCPAP和KTC-1细胞对顺铂的耐药程度高于其他甲状腺癌细胞系,顺铂治疗后BCPAP和KTC-1细胞中检测到DDR通路激活。在昼夜节律基因中筛选影响顺铂疗效的靶点,发现TIMELESS表达与顺铂敏感性和甲状腺癌恶性特征相关。TIMELESS基因敲低可抑制DDR通路的激活,显著增强顺铂在体内和体外的治疗效果。结论新发现的涉及昼夜节律基因和DDR通路的信号通路为顺铂在甲状腺癌中的致敏策略提供了机制见解。因此,TIMELESS可能是甲状腺癌治疗中一个有希望的靶点。
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
CiteScore
8.40
自引率
2.00%
发文量
314
审稿时长
54 days
期刊介绍: Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.
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