Regulation of Stemness by NR1D2 in Colorectal Cancer.

IF 3.9 3区 工程技术 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Sandra Alonso-García, Paula Sánchez-Uceta, Sara Moreno-SanJuan, Jorge Casado, Jose D Puentes-Pardo, Huda Khaldy, David Lopez-Pérez, María Sol Zurita-Saavedra, Cristina González-Puga, Angel Carazo, Josefa León
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引用次数: 0

Abstract

Background: Nuclear Receptor Subfamily 1 Group D Member 2 (NR1D2), a transcription factor that regulates the circadian clock, has been described as an oncogene in colorectal cancer (CRC). In several types of cancer, NR1D2 regulates cancer progression and relapse through cancer stem cells (CSCs), although this aspect has not been studied in CRC. On the other hand, p53 is a tumour suppressor gene that appears mutated in approximately a 50% CRCs. Interestingly, p53 is considered to be a crucial nexus between circadian clock deregulation and cancer. In addition, p53 regulates CSC phenotypes. Methods: We developed an in vitro model in which NR1D2 was silenced in three isogenic cell lines with different p53 status. In addition, we analysed the expression of NR1D2 in a cohort of patients and determined its relationship with the characteristics of patients and tumours. Results: In the in vitro model, NRID2 silencing reduces cell growth and decreases stemness, although only in cells harbouring a wild type p53. In contrast, in cells lacking a functional p53 or harbouring a mutated one, NR1D2 knockout increases cell growth and stemness. In patients, NR1D2 expression correlates with poorly differentiated tumours and high expression of CSCs markers, although only in tumours with a wild type p53, corroborating the results obtained in the in vitro model. Conclusions: Although more research is needed to analyse the mechanism by which NR1D2 regulates stemness in a p53-dependent manner, our results highlight the possibility of using NR1D2 antagonists for treating this type of patient and to develop personalised medicine.

NR1D2在结直肠癌中的调控作用。
背景:核受体亚家族1组D成员2 (NR1D2)是一种调节生物钟的转录因子,已被描述为结直肠癌(CRC)的致癌基因。在几种类型的癌症中,NR1D2通过癌症干细胞(CSCs)调节癌症的进展和复发,尽管这方面尚未在CRC中研究。另一方面,p53是一种肿瘤抑制基因,在大约50%的crc中发生突变。有趣的是,p53被认为是生物钟失调和癌症之间的关键联系。此外,p53调节CSC表型。方法:建立了NR1D2在三种p53状态不同的等基因细胞系中沉默的体外模型。此外,我们分析了NR1D2在一组患者中的表达,并确定了其与患者和肿瘤特征的关系。结果:在体外模型中,NRID2沉默可减少细胞生长并降低干性,尽管仅在含有野生型p53的细胞中。相反,在缺乏功能性p53或含有突变p53的细胞中,敲除NR1D2会增加细胞生长和干细胞性。在患者中,NR1D2表达与低分化肿瘤和CSCs标记物的高表达相关,尽管仅在具有野生型p53的肿瘤中,证实了在体外模型中获得的结果。结论:尽管需要更多的研究来分析NR1D2以p53依赖的方式调节干细胞的机制,但我们的研究结果强调了使用NR1D2拮抗剂治疗这类患者和开发个性化药物的可能性。
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
Biomedicines
Biomedicines Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
5.20
自引率
8.50%
发文量
2823
审稿时长
8 weeks
期刊介绍: Biomedicines (ISSN 2227-9059; CODEN: BIOMID) is an international, scientific, open access journal on biomedicines published quarterly online by MDPI.
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