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

Jun 17, 2025Anti-cancer drugs

Core clock gene problems influence cancer traits and gemcitabine response in bile duct cancer cells

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Genetic deletion of core clock genes BMAL1, PER2, and NR1D1 significantly altered cancer phenotypes in (CCA) cells.

Disruption of circadian rhythm through genetic manipulation of clock genes impacted cancer-related characteristics such as proliferation and apoptosis.
Loss of BMAL1 and NR1D1 increased cell migration, invasion, and activation of processes associated with cancer spread.
BMAL1 deficiency was linked to resistance against the chemotherapy drug gemcitabine.
Repression of PER2 was associated with increased sensitivity to chemotherapy and reduced metastasis.
Core-clock components play a critical role in the mechanisms underlying the malignancy of bile duct cancer.

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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 (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 (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.

Key numbers

BMAL1 knockdown

Increase in migration potential

Disruption of BMAL1 enhances migration in cells.

BMAL1 knockdown

Gemcitabine resistance

Loss of BMAL1 reduces sensitivity to gemcitabine.

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

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