Dysfunction of core clock genes regulates malignant phenotype and gemcitabine sensitivity of cholangiocarcinoma cells.

IF 2.2 4区 医学 Q3 ONCOLOGY
Anti-Cancer Drugs Pub Date : 2025-10-01 Epub Date: 2025-06-17 DOI:10.1097/CAD.0000000000001744
Yin Li, Aimin Zheng, Yangang Cui, Tianbao Liu
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引用次数: 0

Abstract

The circadian clock governs daily rhythms in numerous physiological processes through precise regulation of gene expression and biochemical functions. Dysregulation of the circadian rhythm has been implicated in carcinogenesis and cancer progression. However, the mechanisms by which the circadian clock influences cancer phenotype and chemotherapy resistance, particularly in cholangiocarcinoma (CCA), remain poorly understood. Using cell lines established from primary CCA and metastatic ascites of two male patients, we manipulated core clock genes ( BMAL1 , PER2 , and NR1D1 ) to evaluate their effects on circadian rhythms. We analyzed alterations in circadian phenotypes at dynamic and single time points and assessed their impact on cancer-related phenotypic changes, including proliferation, apoptosis, cell cycle regulation, migration, invasion, and the expression of epithelial-to-mesenchymal transition (EMT) and cancer stem cell markers. Additionally, we examined the impact of circadian disruption on gemcitabine sensitivity. Genetic deletion of BMAL1 , PER2 , and NR1D1 disrupted circadian rhythm and significantly altered cancer phenotypes. Notably, BMAL1 and NR1D1 impairment exacerbated cell migration, invasion, and EMT activation in CCA cells. BMAL1 loss also induced gemcitabine resistance. In contrast, PER2 repression enhanced chemosensitivity and inhibited metastasis. The modulation of the circadian gene triggered phenotypic changes in CCA cells, indicating a crucial involvement of core-clock components in the pathological mechanisms hastening bile duct cancer malignancy. Our findings advance the understanding of regulating CCA malignancy and may offer a novel target for its treatment.

核心时钟基因功能障碍调节胆管癌细胞的恶性表型和吉西他滨敏感性。
昼夜节律钟通过精确调节基因表达和生化功能来控制许多生理过程中的日常节律。昼夜节律失调与癌症发生和癌症进展有关。然而,生物钟影响癌症表型和化疗耐药性的机制,特别是在胆管癌(CCA)中,仍然知之甚少。利用从两名男性患者的原发性CCA和转移性腹水中建立的细胞系,我们操纵核心时钟基因(BMAL1、PER2和NR1D1)来评估它们对昼夜节律的影响。我们分析了动态和单时间点昼夜节律表型的变化,并评估了它们对癌症相关表型变化的影响,包括增殖、凋亡、细胞周期调节、迁移、侵袭、上皮-间质转化(EMT)和癌症干细胞标记物的表达。此外,我们研究了昼夜节律中断对吉西他滨敏感性的影响。BMAL1、PER2和NR1D1的基因缺失破坏了昼夜节律,显著改变了癌症表型。值得注意的是,BMAL1和NR1D1损伤加剧了CCA细胞的细胞迁移、侵袭和EMT激活。BMAL1缺失也诱导了吉西他滨耐药性。相比之下,PER2抑制增强了化疗敏感性并抑制了转移。昼夜节律基因的调节引发了CCA细胞的表型变化,表明核心时钟成分在加速胆管癌恶性发展的病理机制中起着至关重要的作用。我们的发现促进了对CCA恶性肿瘤调控的理解,并可能为其治疗提供新的靶点。
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来源期刊
Anti-Cancer Drugs
Anti-Cancer Drugs 医学-药学
CiteScore
3.80
自引率
0.00%
发文量
244
审稿时长
3 months
期刊介绍: Anti-Cancer Drugs reports both clinical and experimental results related to anti-cancer drugs, and welcomes contributions on anti-cancer drug design, drug delivery, pharmacology, hormonal and biological modalities and chemotherapy evaluation. An internationally refereed journal devoted to the fast publication of innovative investigations on therapeutic agents against cancer, Anti-Cancer Drugs aims to stimulate and report research on both toxic and non-toxic anti-cancer agents. Consequently, the scope on the journal will cover both conventional cytotoxic chemotherapy and hormonal or biological response modalities such as interleukins and immunotherapy. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool.
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