New research reveals circadian clock influences cell growth, metabolism and tumor progression

New research reveals the circadian clock influences cell growth, metabolism and tumor progression Disruption of the circadian clock accelerates intestinal tumorigenesis in vivo.(A) Diagram illustrating the initiation and progression of CRC through APC, Bmal1, and additional mutations. (B) In vivo gut-specific gene targeting strategy for Bmal1 and APC. (VS) Linearized ileum tissue from representative mice of all genotypes. (D) Overview of representative hematoxylin and eosin (H&E) sections – WT stained intestinal Swiss buns, Bmal1−/−, APC+/-and APC+/-;Bmal1−/− mouse. Scale bars, 1 mm. (E) Scatterplot of small intestine polyp count from 30 WT, 30 Bmal1−/−29 APC+/-and 62 APC+/-;Bmal1−/− mouse. (F) Scatterplot of the sizes of individual polyps from the small intestine of APC+/- and APC+/-;Bmal1−/− mouse (not = 8 mice per genotype). (g) Kaplan-Meier survival curve of 9-11 mice per genotype up to 18 months. (H) Scatterplot of number of small intestine polyps from six APC+/- mice maintained under light conditions for 12 hours: 12 hours (12:12) dark and six APC+/- mice maintained under shift disturbance (SD) conditions. (I) Scatterplot of individual small intestine polyp sizes of 12:12 and SD APC+/- mouse. Data represent the mean ± SEM, and statistical significance was determined by one-way analysis of variance (ANOVA) with Tukey’s multiple comparison test for (E), log-rank (Mantel-Cox) test for ( G) and Student’s unpaired test. you test for (F), (H) and (I). The asterisks represent P values ​​of you test or multiple comparisons, with *P < 0.05 and ****P < 0.0001. Credit: Scientists progress (2022). DOI: 10.1126/sciadv.abo2389

In a new study led by the University of California at Irvine, researchers define how the circadian clock influences cell growth, metabolism and tumor progression. Their research also reveals how disruption of the circadian clock affects genome stability and mutations that may further stimulate critical tumor-promoting pathways in the gut.

The study, titled “Circadian clock disruption drives Apc loss of heterozygosity to accelerate colorectal cancer,” was published today in Scientists progress.

In this study, researchers found that both genetic disruption and environmental disruption of the circadian clock contribute to mutation of the adenomatous polyposis coli (APC) tumor suppressor, which is found in the vast majority of human colorectal cancers. (CRC). APC point mutations, deletions, and loss of heterozygosity (LOH) events have been reported in approximately 80% of human CRC cases, and it is these mutations that lead to the initiation of intestinal adenoma development.

“As a society, we are exposed to several environmental factors that influence our biological clock, including night work, prolonged light exposure, changes in sleep/wake cycles, and altered eating behavior,” said said Selma Masri, Ph.D., assistant professor. of biological chemistry at the UCI School of Medicine. “Strikingly, we have seen an alarming increase in several early-onset cancers, including colorectal cancer. The underlying cause for this increased incidence of cancer in adults in their 20s and 30s remains unclear. However, based on our findings, we now believe that disruption of the circadian clock plays an important role.”

According to the National Institutes of Health, there has been an alarming increase in early colorectal cancer among young people. Today, nearly 10% of CRC cases are diagnosed in people under the age of 50, and this trend is steadily increasing. Suspected risk factors include environmental aspects, such as lifestyle and diet factors, which are known to affect the circadian clock.

APC mutations are also associated with second knocks in major oncogenic pathways, including Kras, Braf, p53, and Smad4, and these mutations drive progression to adenocarcinoma, collectively contributing to disease progression. These findings now implicate disruption of the circadian clock in driving additional genomic mutations that are key to accelerating colorectal cancer.

The circadian clock is an internal biological stimulator that governs many physiological processes. Research at Masri Lab primarily focuses on how disruption of the circadian clock is involved in the development and progression of certain types of cancer. Masri lab researchers are actively pursuing further research aimed at defining the impact of the circadian clock on other types of cancer.

Loss of circadian regulation allows increased glucose production during lung cancer

More information:
Sung Kook Chun et al, Circadian clock disruption leads to loss of Apc heterozygosity to accelerate colorectal cancer, Scientists progress (2022). DOI: 10.1126/sciadv.abo2389

Provided by University of California, Irvine

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New research reveals circadian clock influences cell growth, metabolism and tumor progression

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