Extrachromosomal circular DNA (eccDNA) refers to a type of circular DNA that originate from but are likely independent of chromosomes. Due to technological advancements, eccDNAs have recently emerged as multifunctional molecules with numerous characteristics. The unique topological structure and genetic characteristics of eccDNAs shed new light on the monitoring, early diagnosis, treatment, and prediction of cancer. EccDNAs are commonly observed in both normal and cancer cells and function via different mechanisms in the stress response to exogenous and endogenous stimuli, aging, and carcinogenesis and in drug resistance during cancer treatment. The structural diversity of eccDNAs contributes to the function and numerical diversity of eccDNAs and thereby endows eccDNAs with powerful roles in evolution and in cancer initiation and progression by driving genetic plasticity and heterogeneity from extrachromosomal sites, which has been an ignored function in evolution in recent decades. EccDNAs show great potential in cancer, and we summarize the features, biogenesis, evaluated functions, functional mechanisms, related methods, and clinical utility of eccDNAs with a focus on their role in evolution and cancer.

We compared the serum levels of microRNA-155 (miR-155) between subjects with normal response to hepatitis B vaccine and nonresponders. Results showed that serum expression of miR-155 was significantly higher in nonresponders than in responders (6.40 versus 2.55;Z= 2.125,P= 0.034), suggesting that overexpression of miR-155 is correlated with nonresponsiveness to hepatitis B vaccine.

Long-term exposure to benzene or its metabolite, hydroquinone (HQ), can causally contribute to acute myeloid leukemia. Long-noncoding RNAs are essential epigenetic regulators with critical roles in tumor initiation and malignant progression; however, the mechanism by which aberrantly expressed LINC00173 (long intergenic nonprotein coding RNA 173) regulates the pathogenesis of acute myeloid leukemia is not fully understood. Here, we found that the expression of LINC00173 decreased while the expression of DNA methyltransferase 1 (DNMT1) increased, and the methylation of LINC00173 promoter was negatively correlated with LINC00173 expression in GEPIA, CCLE databases, benzene-exposed workers, B-cell non-Hodgkin’s lymphoma, K562, U937, or HQ-induced malignantly transformed TK6 (HQ-MT cells). Furthermore, in 5-aza-2’-deoxycytidine (DNA methyltransferase inhibitor) or trichostatin A (histone deacetylation inhibitor)-treated HQ-MT cells, the expression of LINC00173 was restored by reduced DNA promoter methylation levels. HQ-MT cells with DNMT1 knockout by CRISPR/Cas9 restored the expression of LINC00173 and inhibited the DNA methylation of its promoter as well as enrichment of DNMT1 to promoter. Overexpression of LINC00173 inhibited the expression of DNMT1, cell proliferation, tumor growth, enhanced chemosensitivity to cisplatin, and apoptosis in HQ-MT cells. LINC00173 interacts with DNMT1 to regulate the methylation of LINC00173 promoter. Overall, this study provides evidence that interaction between DNMT1 and LINC00173 regulates the expression of LINC00173 by regulating its promoter methylation level, thus regulating the function of HQ-MT cells in vitro and in vivo, providing a new therapeutic target for benzene-induced tumor.

Evidence from animal and human research suggests that perfluorooctane sulfonate (PFOS), a prevalent persistent organic pollutant (POP), exerts neurotoxic effects, but the precise mechanisms remain unclear. Additionally, the function of activating transcription factor 4 (ATF4), a crucial modulator of cellular metabolism, redox balance, and survival, in PFOS-induced neurotoxicity has not been fully elucidated. In vitro metabolomics studies revealed that PFOS elevated the intracellular concentration of reactive oxygen species (ROS) and lowered the levels of reduced L-glutathione (GSH). Significant alterations in the mRNA and protein expression levels of ferroptosis-related biomarkers, including ferroptosis-related genes [NRF2, nuclear receptor coactivator 4 (NCOA4), KEAP1, xCT/SLC7A11, GPX4, and FTH1], cellular iron, and lipid peroxidation were observed. Moreover, erastin (Ers) exacerbated lipid peroxidation, which was alleviated by ferrostatin-1 (Fer-1) and N-acetyl-L-cysteine (NAC). In mice, PFOS exposure damaged the structure and function of the hippocampus, including decreasing the number of neurons and impairing spatial learning and memory capacity. Importantly, ferroptosis was also observed in vivo, concomitant with the inhibition of ATF4, which was also observed in vitro. ATF4 silencing further increased ROS levels, lipid peroxidation, and ferroptosis induced by PFOS, whereas NAC and Fer-1 abrogated the effects of ATF4 silencing. Treatment with E235, an ATF4 activator, alleviated PFOS-induced ferroptosis. In conclusion, this study revealed that ATF4-mediated ferroptosis is involved in PFOS-induced neurotoxicity, offering novel mechanistic insights into the neurotoxic effects of PFOS and potentially paving the way for new therapeutic strategies.