Stress-induced epinephrine promotes epithelial-to-mesenchymal transition and stemness of CRC through the CEBPB/TRIM2/P53 axis

Abstract

Background Previous studies have indicated that chronic emotional stressors likely participate in the occurrence of cancers. However, direct evidence connecting stress and colorectal cancer development remains almost completely unexplored. Methods Chronic stress mouse model was used to investigate the influence of stress on tumorigenesis. Several major agonists and antagonists of adrenergic receptors were applied to investigate the effects of β-adrenergic signaling on the development of CRC. Chromatin immunoprecipitation assays (CHIP) were used to investigate the binding of p53 and CEBPB to TRIM2 promoter. Mammosphere cultures, Cell Counting Kit-8 (CCK-8) assay, colony-formation assay, scratch wound healing assays, qPCR, immunofluorescence, coimmunoprecipitation and western blotting were used to explore the effect of stress-induced epinephrine on the CEBPB/TRIM2/P53 axis and the progress of CRC cells. Results In this study, we found that stress-induced epinephrine (EPI) promotes the proliferation, metastasis and CSC generation of CRC primarily through the β2-adrenergic receptor. Furthermore, our studies also confirmed that chronic stress decreased the stability of p53 protein by promoting p53 ubiquitination. Results of transcriptome sequencing indicated that TRIM2 was overexpressed in cells treated with EPI. Further studies indicated that TRIM2 could regulate the stability of p53 protein by promoting p53 ubiquitination. Finally, we further proved that CEBPB was regulated by EPI and acts as the upstream transcription factor of TRIM2. Conclusions Our studies proved that stress-induced EPI promotes the development and stemness of CRC through the CEBPB/TRIM2/P53 axis.

Chronic stress promotes gastric cancer progression via the adrenoceptor beta 2/PlexinA1 pathway

“…However, large population-based case-control studies have not confirmed alterations in risk for invasive breast carcinoma with β-blocker use. 39 This suggests that there may be other important factors involved in the process of chronic stress-promoting tumor progression. In this study, we revealed the presence of a chronic stress-activated adrenoceptor beta 2/PlexinA1 signaling pathway, which promoted cell proliferation and EMT of GC.…”

Investigating the crosstalk between chronic stress and immune cells: implications for enhanced cancer therapy

“…The activation of B2AR, MOR, and GSK3 by adrenaline and opioid drugs has been identified as a contributing factor to drug resistance, particularly in triple-negative breast cancer cases ( Rousseau et al, 2022 ). EMT induction in both tongue squamous cell carcinoma and colorectal cancer is facilitated by the activation of distinct signaling pathways ( Liu et al, 2018 ; Zhou et al, 2022 ). The impact of the β2-AR agonist salbutamol on EMT, migration, and invasion has been substantiated through the activation of the ERK phosphorylation pathway ( Lu et al, 2022 ).…”

GABA induced by sleep deprivation promotes the proliferation and migration of colon tumors through miR-223-3p endogenous pathway and exosome pathway

“…Another study reported that MAGI3, as a novel substrate-binding subunit of E3 ligase, can recognize cMYC and regulate its ubiquitination and degradation, thereby regulating colon cancer progression [ 28 ]. Ubiquitination is an essential post-translational modification [ 29 ] and has been investigated in the context of cMYC proteins in various ubiquitination mechanisms in multiple cancers [ 30 – 32 ]. However, whether GABA regulates the ubiquitination of cMYC in colon cancer cells has yet to be studied.…”