Clock gene <i>Per2</i> as a controller of liver carcinogenesis

Mteyrek, Ali; Filipski, Elisabeth; Guettier, Catherine; Okyar, Alper; Lévi, Françis

doi:10.18632/oncotarget.11037

Cited by 60 publications

(63 citation statements)

References 41 publications

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“…In support of human studies, experimental work in rodents documented accelerated tumor growth when mice, engrafted with lung adenocarcinoma or Glasgow osteosarcoma, were exposed to repeated jet lag conditions [9,10]. Similarly, enhanced tumor development has been described in mice with genetic disruption of the circadian clock (although this is not the case for all clock gene mutants) [9,[11][12][13] or surgical lesion of the central clock [14]. Taken together, circadian disruption coincides with increased carcinogenesis and faster tumor growth in a wide range of experimental setups.…”

Section: Circadian Clock Disruption Is Associated With Cancermentioning

confidence: 91%

“…This is a question worth asking, given the circadian regulation of physiological systems relevant to cancer (e.g., immune responses, cell cycle, DNA repair), and the effects of circadian disruption on tumorigenesis (see the first two sections). Indeed, host circadian rhythms have often been found to be disrupted in cancer patients and mouse cancer models [10,12,15,17]. For example, in mice with lung adenocarcinoma, circadian gene expression was largely affected in the liver, with many genes losing rhythmicity, others becoming rhythmic, and some being shifted earlier or later [15].…”

Section: Targeting the Clock In Tumors?mentioning

confidence: 99%

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The tumor circadian clock: a new target for cancer therapy?

Kiessling

Cermakian

2017

Future Oncol.

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Cancer is among the most frequent causes of death in humans. To date, established cancer therapies include surgery, radiation, chemo-and immunotherapy as well as hormonal treatments up to stem cell transplantation. In this editorial, we highlight an additional and so far underestimated factor involved in carcinogenesis and prognosis, namely biological clocks, which should be carefully considered to establish future cancer therapies. Disruption of the circadian clock was documented both in host-tissue and in cancer cells, and functional oscillations were associated with cancer prognosis and survival. We summarize recent advances in the field of chronobiology regarding the role of the host's and tumor-intrinsic circadian clock functions in carcinogenesis.The biological circadian clock controls cancer-related pathways A central clock in the hypothalamus and peripheral clocks in almost all organs and tissues altogether regulate physiological processes in a time of day dependent (circadian) manner. The molecular bases of circadian clocks are cellular oscillations generated by a number of rhythmically expressed interconnected clock genes [1]. Highthroughput experiments on murine tissues showed that in any given cell-type or organ, hundreds or thousands of genes are expressed with a circadian rhythm, and led to the estimation that around 50% of all genes oscillate in at least one organ [2]. As a consequence of this, most cellular and physiological processes show 24 h oscillations. This is the case of many aspects of the immune system, including many immune cells and responses of relevance to cancer [3]. Also, major regulators of the cell cycle and tumor suppressor genes were shown to be regulated by the circadian clock, such as WEE1, c-MYC and p21 [4]. Consistently, cell-cycle progression and proliferation show circadian regulation. Circadian clock disruption is associated with cancerMismatch between the internal clock and the external time disrupts the circadian network, as reported for example in shift workers [5], and has been associated with a wide range of pathologies and disease states including cancer [4]. Mounting evidence from human-based epidemiological studies suggested an effect of circadian disruption during shift work on cancer risk. For example, the risk to develop breast cancer was extensively increased in nurses exposed to long-term rotating night shift work [6]. Similar results were obtained for prostate cancer risk in night shift workers [7]. Out of note, in 2007 an agency of the WHO has classified night shift work leading to circadian disruption as 'probably carcinogenic' to humans [8]. Since then, there has been growing interest in understanding how circadian disruption may play a role in cancer development and progression. In support of human studies, experimental work in rodents documented accelerated tumor growth when mice, engrafted with lung adenocarcinoma or Glasgow osteosarcoma, were exposed to repeated jet lag conditions [9,10]. Similarly, enhanced tumor development has been described in mi...

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Section: Circadian Clock Disruption Is Associated With Cancermentioning

confidence: 91%

Section: Targeting the Clock In Tumors?mentioning

confidence: 99%

The tumor circadian clock: a new target for cancer therapy?

Kiessling

Cermakian

2017

Future Oncol.

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“…Mteyrek assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine exposure, according to constitutive PER2 mutation [34]; PER2 mutation severely deregulated liver gene or protein expressions related to three cancer endpoints, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold [34]. Previously, it was demonstrated that mutation or knockout of clock genes PER2, CRY1/CRY2 or BMAL1 also accelerated the development of lymphomas following whole body exposure to γ radiations [35,36].…”

Section: Clock-work Dysfunction and Cancermentioning

confidence: 99%

The Role of Biological Clock in Gynecologic Cancer

Karoutsou¹,

Karoutsos²,

Karoutsos³

2017

Arch Can Res

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Disruption in coordinated co-expression of clock genes, like Period genes mutations, is linked with the increased risk of lung, gastrointestinal, hematologic and gynecologic cancers. Several clock genes have been found to functionally interplay with regulators of the cell cycle. It is suggested that abnormal cell cycle function in cancer could also be a consequence of a disrupted biological clock. Chrono-disruption, being studied in different cancer entities, including the gynecologic cancer, could provide time set intervention in cancer therapeuticschronotherapy in a 24 h-period.

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“…Per2 mutation accelerates hepatocarcinogenesis through uncontrolled proliferation, genomic instability and tumor promoting inflammation. This mutation increases HCC several folds without any significant effect on CCA development …”

mentioning

confidence: 97%

“…Circadian disruption induced by Per2 mutation, constant light or chronic jet lag exposure has been shown to promote DEN‐induced liver carcinogenesis, resulting in increased formation of a majority of HCC and few CCA in rats and mice . DEN is usually used for liver cancer initiation (2–4 weeks of DEN exposure) and induces the formation of dysplastic foci with altered hepatocytes.…”

mentioning

confidence: 99%

Critical cholangiocarcinogenesis control by cryptochrome clock genes

et al. 2017

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A coordinated network of molecular circadian clocks in individual cells generates 24-hr rhythms in liver metabolism and proliferation. Circadian disruption through chronic jet lag or Per2 clock gene mutation was shown to accelerate hepatocarcinoma development in mice. As divergent effects were reported for clock genes Per and Cry regarding xenobiotic toxicity, we questioned the role of Cry1 and Cry2 in liver carcinogenesis. Male WT and Cry1 Cry2 mice (C57Bl/6 background) were chronically exposed to diethylnitrosamine (DEN) at ZT11. Rest-activity and body temperature rhythms were monitored using an implanted radiotransmitter. Serum aspartate and alanine aminotransferases (AST and ALT) were determined on four occasions during the progression stage. After 7 months, serum alkaline phosphatases (ALP) were determined, and livers were sampled for microscopic tumor nodule counting and histopathology. Five months after initiation of DEN treatment, we found that Cry1 Cry2 mice developed severe liver dysplasia, as evident from the increased AST, ALT and ALP levels, as compared to WT mice. DEN exposure induced primary liver cancers in nearly fivefold as many Cry1 Cry2 mice as compared to WT mice (p = 0.01). Microscopic study revealed no difference in the average number of hepatocarcinomas and a nearly eightfold increase in the average number of cholangiocarcinomas in Cry1 Cry2 mice, as compared to WT mice. This study validated the hypothesis that molecular circadian clock disruption dramatically increased chemically induced liver carcinogenesis. In addition, the pronounced shift toward cholangiocarcinoma in DEN exposed Cry1 Cry2 mice revealed a critical role of the Cry clock genes in bile duct carcinogenesis.

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Clock gene Per2 as a controller of liver carcinogenesis

Cited by 60 publications

References 41 publications

The tumor circadian clock: a new target for cancer therapy?

The tumor circadian clock: a new target for cancer therapy?

The Role of Biological Clock in Gynecologic Cancer

Critical cholangiocarcinogenesis control by cryptochrome clock genes

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