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Circadian disruption: from mouse models to molecular mechanisms and cancer therapeutic targets

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Abstract 

The circadian clock is a timekeeping system for numerous biological rhythms that contribute to the regulation of numerous homeostatic processes in humans. Disruption of circadian rhythms influences physiology and behavior and is associated with adverse health outcomes, especially cancer. However, the underlying molecular mechanisms of circadian disruption-associated cancer initiation and development remain unclear. It is essential to construct good circadian disruption models to uncover and validate the detailed molecular clock framework of circadian disruption in cancer development and progression. Mouse models are the most widely used in circadian studies due to their relatively small size, fast reproduction cycle, easy genome manipulation, and economic practicality. Here, we reviewed the current mouse models of circadian disruption, including suprachiasmatic nuclei destruction, genetic engineering, light disruption, sleep deprivation, and other lifestyle factors in our understanding of the crosstalk between circadian rhythms and oncogenic signaling, as well as the molecular mechanisms of circadian disruption that promotes cancer growth. We focused on the discoveries made with the nocturnal mouse, diurnal human being, and cell culture and provided several circadian rhythm-based cancer therapeutic strategies.

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Abbreviations

SCN:

Suprachiasmatic nuclei

TTFLs:

Transcription-translation negative feedback loops

ARNTL:

Hydrocarbon receptor nuclear translocator-like protein 1

BMAL1:

Brain and muscle ARNT-like protein1

CLOCK:

Circadian locomotor output cycles kaput

PER1:

Period 1

PER2:

Period 2

PER3:

Period 3

CRY1:

Cryptochrome 1

CRY2:

Cryptochrome 2

NR1D1:

Nuclear receptor subfamily 1 group D member 1

NR1D2:

Nuclear receptor subfamily 1 group D member 2

CK1δ:

Casein kinase 1δ

ROR:

Retinoic acid receptor-related orphan receptor

RORE:

ROR-response element

PAR-bZIP:

Proline and acidic amino acid-rich basic leucine zipper

DBP:

D-element-binding protein

TEF:

Thyrotrophic embryonic factor

HLF:

Hepatic leukemia factor

NFIL3:

Nuclear factor interleukin 3-regulated

AMPK:

AMP-activated protein kinase

mTOR:

Mechanistic target of rapamycin

HIF1α:

Hypoxia-inducible factor-1α

MAPKs:

Mitogen-activated protein kinases

MAPK8:

MAP kinases 8

GSK3β:

Glycogen synthase kinase 3 beta

ATF4:

Activating transcription factor 4

CRE:

CAMP-response element

NRF2:

Nuclear factor erythroid 2-related factor 2

PPARs:

Peroxisome proliferator-activated receptors

RXR:

Retinoid X receptor

PPRE:

PPAR response element

PGC-1α:

PPARγ coactivator 1α

CDK1:

Cyclin-dependent kinase 1

CREB:

CAMP response element-binding protein

CBP:

CREB-binding protein

HDAC3:

Histone deacetylase 3

ipRGCs:

intrinsically photosensitive retinal ganglion cells

IGL:

Intergeniculate leaflet

GOS:

Glasgow osteosarcoma

AAV:

Adeno-associated virus

KD:

Knockdown

KO:

Knockout

Cre:

cyclization recombination recombinase

FRT:

Flippase recognition target

ABC:

ATP-binding cassette

ABCG5:

ABC subfamily G member 5

ABCG8:

ABC subfamily G member 8

NAFLD:

Non-alcoholic fatty liver disease

CRC:

Colorectal cancer

OS:

Overall survival

PFS:

Progression-free survival

HCC:

Hepatocellular carcinoma

CAR:

Constitutive androstane receptor

ROS:

Reactive oxygen species

LSC:

Leukemia stem cells

EMT:

Epithelial to mesenchymal transition

OSCC:

Oral squamous cell carcinoma

GSC:

Glioma stem-like cells

Aldh3a1:

Aldehyde dehydrogenase 3a1

DKO:

Double KO

DEN:

Diethylnitrosamine

RHT:

Retinohypothalamic tract

CJL:

Chronic jet lag

LD:

Light-dark

DD:

Constant darkness

NK:

Nature killer

LL:

Constant light

LAN:

Light at night

DOX:

Doxorubicin

BMI:

Body mass index

WTE:

Wrong time eating

Th17:

T-helper cell 17

Treg:

Regulatory T

TME:

tumor microenvironment

TRE:

Time-restricted eating

HFD:

High-fat diet

RTE:

Right time eating

SD:

Sleep deprivation

DCs:

dendritic cells

MPM:

Multiple platform method

MDSCs:

myeloid-derived suppressor cells

PSD:

Paradoxical sleep deprivation

IL-1β:

interleukin-1β

ASD:

Acute sleep deprivation

TAMs:

tumor-associated macrophages

CSD:

Chronic sleep deprivation

SF:

Sleep fragmentation

NAT:

N-acetyltransferase

HIOMT:

Hydroxy indole-O-methyltransferase

UEGs:

Universally expressed genes

GABA:

G-Aminobutyric acid

PACAP:

Cyclase-activating peptide

ANS:

Autonomic nervous system

PVN-SCG:

Paraventricular nucleus-superior cervical ganglia

TTX:

Tetrodotoxin

VIP:

Vasoactive intestinal peptide

CNO:

clozapine N-oxide

DREADD:

Designer receptors exclusively activated by designer drugs

Tc17 CD8+ :

type 17 effector

NOB:

Natural flavonoid nobiletin

PFKFB3:

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3

DIO:

Diet-induced obese

G6PD:

glucose-6-phosphate 1-dehydrogenase

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Acknowledgements

We thank the members from the Academy of Integrative Medicine for the helpful discussions. We apologize to the scientists whose work could not be cited in this review due to space limitations.

Funding

This work was supported by the National Science Foundation of China (82172947 to F.H.).

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Authors and Affiliations

  1. Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Yu Wang, Haidong Guo & Feng He

  2. Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Haidong Guo

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YW, HDG, and FH conceived the structure of the manuscript and revised the manuscript. YW wrote the manuscript and made the figures. HDG and FH reviewed and edited the manuscript. All authors read and approved the final manuscript.

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Wang, Y., Guo, H. & He, F. Circadian disruption: from mouse models to molecular mechanisms and cancer therapeutic targets. Cancer Metastasis Rev 42, 297–322 (2023). https://doi.org/10.1007/s10555-022-10072-0

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