AI Article Synopsis

  • Circadian rhythms regulate key molecular processes in living organisms, and their disruption can lead to severe health issues, including cancer.
  • A systems biology approach was used to analyze various colorectal and skin cancer cell lines, revealing distinct patterns of circadian oscillation and specific genes that differentiate these patterns.
  • The study identified the RAS/MAPK pathway's role in disturbing circadian rhythms, showing that oncogene overexpression (like RAS) can negatively impact the circadian clock's functioning.

Article Abstract

Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038477PMC
http://dx.doi.org/10.1371/journal.pgen.1004338DOI Listing

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