Epidemiological studies have linked chronodisruption to an increased incidence of specific human malignancies such as prostate and breast cancer. Based on GLOBOCAN predictions, liver cancer is expected to increase more than 50% by 2040 probably due to alcohol consumption and hepatitis virus infection, but also to the current lifestyle. In our lab, we are interested in understanding whether chronodisruption is able to modify the hepatic molecular clock and/or downstream pathways to change cellular landscape for malignancies´ growth. Our preliminary data show that a mild stress induced by simulating social jet-lag induces a shift in the expression of hepatic Bmal1 and Clock genes inducing downstream changes in key pathways for cancer biology. Moreover, we are describing the exosomes profile of jet-lagged mice for further use it as a biomarker in liquid biopsy of chronodisruption-induced liver cancer.

A representative group of male mice were subjected only to a 4 hours delay in the switch on/off of the light schedule during two consecutive weekends, simulating an acute protocol of social jet lag. Control mice (CTL) had a 12h light schedule from 8 am to 20 pm and a 12h dark schedule from 20 pm to 8 a. In the other hand, jet-lagged mice had also a 12 light/dark schedule but from 12 pm to 00 am (light) and from 00 am to 12 pm (dark), so they were delayed 4h respecting their control group.

Western blot analysis of the liver reveals this social jet lag is enough to modify or delay the circadian pattern of molecular clock genes Bmal1, Clock and Per1, being downregulated or delayed in jet-lagged mice in every time-point collected (ZT0, ZT4, ZT12, ZT16, ZT20) except at ZT8 (16pm), when control mice exhibit less proteins of the molecular clock than mice subjected to jet-lag. Also, we have analyzed metabolic pathways related with the storage (Acls1) and de novo synthesis (Fasn) of free fatty acid in the liver, discovering an opposite answer on the hepatic function of fat synthesis between both groups, manifesting some relevant biological facts, for example, that jet-lagged mice have more Fasn during fasting at night than control mice (because mice are nocturnal animals). Expression of autophagy biomarkers as Lc3a and Atg7 reflects as well that this process mainly occurs in the jet-lagged group during the night and the early morning, probably derived from the chronodisruption stimulus. Transcriptional analysis performed through qPCR at the same 6 time points to study mRNA expression of these genes shows that there is less Bmal1 mRNA expression during the dark phase and less Clock mRNA at 12am, although jet-lagged mice exhibit more Clock mRNA at 12pm than their control group. Finally, with the main goal of studying the way whether the liver crosstalks with other organs, we have started to describe liver extracellular vesicles (EVs), their fold enrichment and size differences, seeing that those from jet-lagged mice show higher size than control mice. This sighting is a first approach to understand how liver is affected by a mild chronodisruption stimuli.

Chronodisruption, as a loss of our inner biological rhythm synchronization with environmental stimuli changes like day/night dichotomy is related with the modification of several molecular pathways in the liver that could drive to human diseases as an inflammatory status, and finally, whith a chronic exposure, to the development of liver diseases including tumor development and cancer.