The circadian clock and hypoxia in tumor cell de-differentiation and metastasis

Jensen, Lasse D.

doi:10.1016/j.bbagen.2014.10.025

Cited by 19 publications

(19 citation statements)

References 86 publications

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“…In 2015, Jensen reviewed recent findings on the role of circadian rhythms and hypoxia in cancer and metastasis, and concluded that circadian rhythms and hypoxia are involved in tumor metastasis at all levels from pathological deregulation of the cells to the tissues and the whole organism. Pathological tumor blood vessels caused hypoxia and disruption in circadian rhythmicity, which in turn commuted to tumor metastasis (37). According to our previous results, expression of hClock was associated with the overexpression of HIF-1α, ARNT and VEGF in CRC specimens (26).…”

Section: Discussionmentioning

confidence: 76%

Upregulation of circadian gene 'hClock' contribution to metastasis of colorectal cancer

Wang

Sun

Lü

et al. 2017

International Journal of Oncology

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Recent studies have shown that disruption of the circadian rhythm was one of the endogenous factors contributing to tumorigenesis of various human malignancies, including colorectal cancer (CRC). However, the roles of circadian genes in the development of CRC are still unexplored. In this study, we investigated the expression pattern and the underlying mechanism of human Clock gene (hClock) in CRC progression. Multiple methods such as qRT-PCR, immunohistochemistry, and western blotting were performed to evaluate the expression pattern of the gene hClock, as well as to observe the changes of angiogenesis-related proteins and EMT-related proteins. Transwell cell migration assays and an animal tumor metastasis model were used to examine the impact of hClock on the metastatic ability of CRC cells in vitro and in vivo. Our results showed that the expression level of hClock significantly increased in human CRC tissues, which strongly associated with late TNM stage and positive lymph node metastasis. Moreover, a higher level of hClock expression was found in CRC cell lines with a higher metastatic potential. Furthermore, ectopic expression of hClock promoted the migration of SW480 CRC cells, while knockdown of hClock inhibited the tumor metastasis of SW620 CRC cells, and targeting hClock by shRNA effectively suppressed the metastatic ability of SW620 CRC cells in nude mice. Finally, we found that overexpression of hClock enhanced the expression of angiogenesis-related genes such as HIF-1α, ARNT and VEGF, and promoted epithelial-mesenchymal (-like) transition (EMT) in CRC cells, both of which are considered to be critical for tumor progression. These findings suggest that upregulation of the circadian gene hClock plays an important role in metastasis of colorectal cancer.

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Section: Discussionmentioning

confidence: 76%

Upregulation of circadian gene 'hClock' contribution to metastasis of colorectal cancer

Wang

Sun

Lü

et al. 2017

International Journal of Oncology

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“…Hypoxic responses are gated by the circadian clock and at the genomic level, BMAL1 and HIF-1A synergistically interact to co-regulate downstream genes (27). Crosstalk between hypoxia and the clock has profound implications on cancer pathophysiology (44,45). We reason that tumour hypoxia could synergise with the circadian clock to impact disease progression.…”

Section: Dysregulated Circadian Timekeeping Is Associated With Malignmentioning

confidence: 98%

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

Lai

2019

Preprint

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The circadian clock governs a large variety of fundamentally important physiological processes in all three domains of life. Consequently, asynchrony in timekeeping mechanisms could give rise to cellular dysfunction underpinning many disease pathologies including human neoplasms. Yet, detailed pancancer evidence supporting this notion has been limited. In an integrated approach uniting genetic, transcriptomic and clinical data of 21 cancer types (n=18,484), we interrogated copy number and transcript profiles of 32 circadian clock genes to identify putative loss-of-function (Clock Loss ) and gainof-function (Clock Gain ) players. Kaplan-Meier, Cox regression and receiver operating characteristic analyses were employed to evaluate the prognostic significance of both gene sets. Clock Loss and Clock Gain were associated with tumoursuppressing and tumour-promoting roles respectively. Downregulation of Clock Loss genes resulted in significant higher mortality rates in five cancer cohorts (n=2,914): bladder (P=0.027), glioma (P<0.0001), pan-kidney (P=0.011), clear cell renal cell (P<0.0001) and stomach (P=0.0007). In contrast, patients with high expression of oncogenic Clock Gain genes had poorer survival outcomes (n=2,784): glioma (P<0.0001), pan-kidney (P=0.0034), clear cell renal cell (P=0.014), lung (P=0.046) and pancreas (P=0.0059). Both gene sets were independent of other clinicopathological features to permit further delineation of tumours within the same stage. Circadian reprogramming of tumour genomes resulted in activation of numerous oncogenic pathways including those associated with cancer stem cells, suggesting that the circadian clock may influence self-renewal mechanisms. Within the hypoxic tumour microenvironment, circadian dysregulation is exacerbated by tumour hypoxia in glioma, renal, lung and pancreatic cancers, resulting in additional death risks. Tumour suppressive Clock Loss genes were negatively correlated with hypoxia inducible factor-1A targets in glioma patients, providing a novel framework for investigating the hypoxia-clock signalling axis. Loss of timekeeping fidelity promotes tumour progression and influences clinical outcomes. Clock Loss and Clock Gain may offer novel druggable targets for improving patient prognosis. Both gene sets can be used for patient stratification in adjuvant chronotherapy treatment. Emerging interactions between the circadian clock and hypoxia may be harnessed to achieve therapeutic advantage using hypoxia-modifying compounds in combination with firstline treatments. circadian clock | hypoxia | oncogene | tumour suppressor | gain-of-function | loss-of-function | pan-cancer | glioma | renal cancer Correspondence: alvina.lai@ndm.ox.ac.uk

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“…Hypoxia signaling and the circadian clock are closely related and heavily cross-communicating pathways ( 5 ). Both pathways are evolutionarily ancient, presenting the first molecular mechanisms allowing living organisms to adapt to environmental stimuli on earth (light/dark cycles and the strongly oxidative environment respectively) ( 47 – 50 ).…”

Section: Hypoxia and The Circadian Clock–to Sides Of The Same Coin?mentioning

confidence: 99%

“…On the other hand, disruptions in circadian physiology may also lead to stress and de-regulation of the chromaffin cells, potentially increasing the risk of PCC development ( 3 ). In addition, PCC pathology is often genetically linked to disrupted oxygen sensing and hypoxia signaling ( 1 , 4 ), which in turn is intimately coupled to regulation of the cellular circadian clock ( 5 ) and to endocrine as well as local regulation of cardiovascular function and metabolism ( 6 ). As such, PCC represents a malignancy in which multiple aspects of hypoxia and circadian regulation of endocrine functions are affected, providing a strong case for understanding such interplay in more detail.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Signaling and Circadian Disruption in and by Pheochromocytoma

2018

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Disruption of the daily (i.e., circadian) rhythms of cell metabolism, proliferation and blood perfusion is a hallmark of many cancer types, perhaps most clearly exemplified by the rare but detrimental pheochromocytomas. These tumors arise from genetic disruption of genes critical for hypoxia signaling, such as von Hippel-Lindau and hypoxia-inducible factor-2 or cellular metabolism, such as succinate dehydrogenase, which in turn impacts on the cellular circadian clock function by interfering with the Bmal1 and/or Clock transcription factors. While pheochromocytomas are often non-malignant, the resulting changes in cellular physiology are coupled to de-regulated production of catecholamines, which in turn disrupt circadian blood pressure variation and therefore circadian entrainment of other tissues. In this review we thoroughly discuss the molecular and physiological interplay between hypoxia signaling and the circadian clock in pheochromocytoma, and how this underlies endocrine disruption leading to loss of circadian blood pressure variation in the affected patients. We furthermore discuss potential avenues for targeting these tumor-specific pathophysiological mechanisms therapeutically in the future.

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The circadian clock and hypoxia in tumor cell de-differentiation and metastasis

Cited by 19 publications

References 86 publications

Upregulation of circadian gene 'hClock' contribution to metastasis of colorectal cancer

Upregulation of circadian gene 'hClock' contribution to metastasis of colorectal cancer

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

Hypoxia Signaling and Circadian Disruption in and by Pheochromocytoma

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