Core Circadian Clock Proteins as Biomarkers of Progression in Colorectal Cancer

Aroca-Siendones, Inés; Moreno-SanJuan, Sara; Puentes-Pardo, Jose D.; Verbeni, Michela; Arnedo, Javier; Escudero-Feliú, Julia; García-Costela, María; García-Robles, Adelina; Carazo, Ángel; León, Josefa

doi:10.3390/biomedicines9080967

Cited by 6 publications

(18 citation statements)

References 58 publications

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“…In a recent study, 258 CRC patients and 66 controls were analysed to evaluate the prognostic significance of CC proteins in CRC and to establish circadian clock biomarkers of CRC progression [ 48 ]. The study found that low expressions of ARNTL or PER2 were significantly associated with metastasis at the moment of disease diagnosis and suggested ARNTL and CRY1 as biomarkers of CRC patient survival and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Core-Clock Genes Regulate Proliferation and Invasion via a Reciprocal Interplay with MACC1 in Colorectal Cancer Cells

Basti

Malhan

Dumbani

et al. 2022

Cancers

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The circadian clock coordinates the timing of several cellular processes including transcription, the cell cycle, and metabolism. Disruptions in the clock machinery trigger the abnormal regulation of cancer hallmarks, impair cellular homeostasis, and stimulate tumourigenesis. Here we investigated the role of a disrupted clock by knocking out or knocking down the core-clock (CC) genes ARNTL, PER2 or NR1D1 in cancer progression (e.g., cell proliferation and invasion) using colorectal cancer (CRC) cell lines HCT116, SW480 and SW620, from different progression stages with distinct clock phenotypes, and identified mechanistic links from the clock to altered cancer-promoting cellular properties. We identified MACC1 (metastasis-associated in colon cancer 1), a known driver for metastasis and an EMT (epithelial-to-mesenchymal transition)-related gene, to be significantly differentially expressed in CC manipulated cells and analysed the effect of MACC1 manipulation (knockout or overexpression) in terms of circadian clock phenotype as well as cancer progression. Our data points to a bi-directional MACC1-circadian clock interplay in CRC, via CC genes. In particular, knocking out MACC1 reduced the period of oscillations, while its overexpression increased it. Interestingly, we found the MACC1 protein to be circadian expressed in HCT116 WT cells, which was disrupted after the knockout of CC genes, and identified a MACC1-NR1D1 protein–protein interaction. In addition, MACC1 manipulation and CC knockout altered cell invasion properties of HCT116 cells, pointing to a regulation of clock and cancer progression in CRC, possibly via the interaction of MACC1 with core-clock genes.

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Section: Discussionmentioning

confidence: 99%

Core-Clock Genes Regulate Proliferation and Invasion via a Reciprocal Interplay with MACC1 in Colorectal Cancer Cells

Basti

Malhan

Dumbani

et al. 2022

Cancers

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“…Mostafaie et al (40) demonstrated a correlated decrease in Per1 and estrogen receptor-β in colorectal tumours. Furthermore, six studies reported that Per2 expression was significantly decreased in tumour tissues (39,(48)(49)(50)(51)(52). Hasakova et al (50,53) found that Per2 was downregulated in tumour tissues of male patients with CRC, but Krugluger et al (45) determined that Per2 expression exhibited no differences in colon tumour tissues; the following six studies also confirmed this (38,(40)(41)(42)47).…”

Section: Associations Between Crc and Circadian Clock Genesmentioning

confidence: 94%

“…It was determined that high Cry1 expression was correlated with poor OS rates in patients with CRC (73). Another study also indicated that high expression of Cry1 was associated with lower OS and disease-free survival at five years in patients with CRC (49). Hasakova et al (50,72) indicated that the expression of Cry1 and Cry2 was correlated differently with sex or tumour location in colon carcinoma tissues.…”

Section: Associations Between Crc and Circadian Clock Genesmentioning

confidence: 99%

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Circadian clock as a possible control point in colorectal cancer progression (Review)

Rao

Lin

2022

Int J Oncol

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The circadian rhythm is generated at the cellular level by a molecular clock system that involves specific genes. Studies have revealed that circadian clock disruption is a control point in cancer progression. Colorectal cancer (CRC) is one of the cancers closely associated with circadian disruption. In the present review, the involvement of the circadian clock in CRC development was summarized. Abnormal expression of certain clock genes has been found in patients with CRC and their correlation with clinicopathological features has also been explored. The period and cryptochrome 2 (Cry2), Sirtuin1 (SIRT1) and neuronal PAS domain protein 2 (NPAS2) genes were reported to have tumour suppressor properties. Conversely, Cry1, brain and muscle ARNT-like-1, circadian locomotor output cycles kaput (CLOCK) and timeless may aggravate CRC progression, but these findings are not consistent and require to be confirmed by further research. Circadian scheduling also indicated advantages in chemotherapy treatments for patients with CRC by increasing the maximum tolerated doses and decreasing toxicities. Dysfunction of the molecular CLOCK system disrupted cellular processes to accelerate colon tumorigenesis, such as metabolism, cell cycle, DNA damage repair, proliferation and apoptosis, epithelial-mesenchymal transition and stemness. The clock gene network and how the dynamics of the system influence CRC were discussed.

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“…The central clock is found in the suprachiasmatic nucleus (SCN) of the hypothalamus, whereas peripheral clocks are located in different tissues and organs (muscle, adipose tissue, liver, pancreas, etc.) [ 11 ]. Light is the principal external stimulus and acts by regulating the activity of the so-called circadian pacemaker or central clock [ 11 , 12 ].…”

Section: Introduction: Circadian Rhythmsmentioning

confidence: 99%

Chronotherapy: Circadian Rhythms and Their Influence in Cancer Therapy

Amiama-Roig

Verdugo‐Sivianes

Carnero

et al. 2022

Cancers

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Living organisms present rhythmic fluctuations every 24 h in their behavior and metabolism to anticipate changes in the environment. These fluctuations are controlled by a very complex molecular mechanism, the circadian clock, that regulates the expression of multiple genes to ensure the right functioning of the body. An individual’s circadian system is altered during aging, and this is related to numerous age-associated pathologies and other alterations that could contribute to the development of cancer. Nowadays, there is an increasing interest in understanding how circadian rhythms could be used in the treatment of cancer. Chronotherapy aims to understand the impact that biological rhythms have on the response to a therapy to optimize its action, maximize health benefits and minimize possible adverse effects. Clinical trials so far have confirmed that optimal timing of treatment with chemo or immunotherapies could decrease drug toxicity and increase efficacy. Instead, chronoradiotherapy seems to minimize treatment-related symptoms rather than tumor progression or patient survival. In addition, potential therapeutic targets within the molecular clock have also been identified. Therefore, results of the application of chronotherapy in cancer therapy until now are challenging, feasible, and could be applied to clinical practice to improve cancer treatment without additional costs. However, different limitations and variables such as age, sex, or chronotypes, among others, should be overcome before chronotherapy can really be put into clinical practice.

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Core Circadian Clock Proteins as Biomarkers of Progression in Colorectal Cancer

Cited by 6 publications

References 58 publications

Core-Clock Genes Regulate Proliferation and Invasion via a Reciprocal Interplay with MACC1 in Colorectal Cancer Cells

Core-Clock Genes Regulate Proliferation and Invasion via a Reciprocal Interplay with MACC1 in Colorectal Cancer Cells

Circadian clock as a possible control point in colorectal cancer progression (Review)

Chronotherapy: Circadian Rhythms and Their Influence in Cancer Therapy

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