A new study shows that the circadian clock affects cell growth, metabolism and tumor progression

A) Apc, Bmal1 and a schematic diagram describing the initiation and progression of CRC through additional mutations. (B) Bmal1 the and Apc In vivo gut-specific gene targeting strategy for. (C) Linear leaf tissue from representative mice of all genotypes. (D) overview of representative sections of hematoxylin and eosin (H&E)–WT, Bmal1−/−thin swiss rolls painted from Apc+/−the and Apc+/−;Bmal1−/− mice. Scale bars, 1 mm. (E) 30 WT, 30 Bmal1−/−29 Apc< баштап ичке ичеги полиптеринин санынын чачыранды графиги sup>+/− and 62 Apc+/−;Bmal1−/− mouse . (F) Apc+/− the and Apc Scatter plot of individual polyp sizes in the small intestine +/−;Bmal1−/− mice (n = 8 mice per genotype). (G) Kaplan-Meier survival curves for genotype 9-11 mice up to 18 months of age. (H) of six kept under 12 hours of light Apc+/− Scatter plot of small intestinal polyps in mice: 12 h (12:12) dark conditions and six Apc+/− mice were maintained under shift-disrupted (SD) conditions. (I) 12:12 and SD Apc+/− Scatterplot of individual polyp sizes from the small intestine of mice. Data represent 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 < тести менен аныкталган. i>ttest (F), (H) and (I). Asterisks t tested P values ​​or *P denotes multiple comparisons with < 0.05 and ****P < 0.0001. Credit: Achievements of science (2022). DOI: 10.1126/sciadv.abo2389″ width=”800″ height=”530″/>

Disruption of the circadian clock accelerates intestinal tumors in vivo.THE) using a schematic diagram depicting the initiation and progression of CRC Apc, Bmal1, and additional mutations. (V) for an in vivo gut-specific gene targeting strategy Bmal1 the and Apc. (Ch) Linear intestinal tissues from representative mice of all genotypes. (D) overview of representative sections of hematoxylin and eosin (H&E)–stained small intestine Swiss rolls from WT, Bmal1−/−, Apc+/−the and Apc+/−;Bmal1−/− mice. Scale bars, 1 mm. (THE AND) Scatter plot of small intestinal polyps 30 WT, 30 Bmal1−/−29 Apc+/−and 62 Apc+/−;Bmal1−/− mice. (F) scatter plot of individual polyp sizes from the small intestine Apc+/− the and Apc+/−;Bmal1−/− mice (do not = 8 mice per genotype). (G) Kaplan-Meier survival curves for genotype 9-11 mice up to 18 months of age. (H) The number of scattered small intestinal polyps is six Apc+/− mice under 12-hour light:12-hour (12:12) dark conditions and six Apc+/− mice maintained under shift-disrupted (SD) conditions. (I) 12:12 and SD is a scatter plot of individual polyp sizes from the small intestine Apc+/− mice. Data represent 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) for (G), and Student’s unpaired t test. t Test for (F), (H) and (I). Asterisks represent P and values t test or multiple comparison, with *P < 0.05 and ****P < 0.0001. Credit: Science Advances (2022). DOI: 10.1126/sciadv.abo2389

Researchers at the University of California, Irvine, have discovered how the circadian clock affects cell growth, metabolism and tumor progression. Their research also sheds light on how disruption of the circadian clock affects genome stability and mutations that predispose to tumorigenesis in the gut.

The study, titled “Circadian clock disruption leads to loss of Apc heterozygosity,” accelerates colorectal cancer. Science Advances.

In this study, researchers found that genetic disruption of the circadian clock and environmental disturbances contribute to mutations in the adenomatous polyposis coli (APC) tumor suppressor 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 percent of human CRC cases, and it is these mutations that drive the initiation of intestinal adenoma development.

“As a society, we are exposed to several environmental factors that affect our biological clock, including night shift work, light duration, changes in sleep/wake cycles, and changes in eating behaviors,” said Selma Masri, Ph.D., assistant professor. in Biological Chemistry at the UCI School of Medicine. “Surprisingly, we’ve seen an alarming increase in cancers in several age groups, including colorectal cancer. The main reason for the increase in 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-onset colon cancer among young adults. Today, nearly 10 percent of CRC cases are now diagnosed in people younger than 50 years of age, and this trend is steadily increasing. Suspected risk factors include aspects of the environment, such as lifestyle and dietary factors, that affect the circadian clock.

APC mutations are also associated with secondary hits in key oncogenic pathways, including Kras, Braf, p53, and Smad4, and these mutations enhance progression to adenocarcinoma and contribute to overall disease progression. These findings now implicate disruption of the circadian clock in driving additional genomic mutations that are important for accelerating colorectal cancer.

The circadian clock is an internal biological pacemaker that controls many physiological processes. Research in Masri’s lab primarily focuses on how disruption of the circadian clock is involved in the development and progression of certain types of cancer. Masri’s lab researchers are actively pursuing further studies aimed at determining how the circadian clock affects other types of cancer.


Loss of circadian regulation allows increased glucose production in lung cancer


More information:
Sung Kook Chun et al., Circadian clock disruption causes loss of Apc heterozygosity and accelerates colon cancer, Science Advances (2022). DOI: 10.1126/sciadv.abo2389

Courtesy of University of California, Irvine

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