Significant CircRNAs in liver cancer stem cell exosomes: mediator of malignant propagation in liver cancer?

Abstract Hepatocellular carcinoma (HCC), one of the most prevalent forms of cancer worldwide, presents a significant global healthcare challenge. Cancer stem cells (CSCs), which can influence neighboring non-CSCs, are believed to play a crucial role in tumor growth and resistance to treatment, but the specific mechanisms and mediators are not fully understood. Regulation of the CSC state is considered an ideal therapeutic strategy both in the early stages of tumor formation and within established tumors. Exosomes have emerged as key players in intercellular communication, similar to classical hormone signaling, and are essential for facilitating communication between cells in liver cancer. Here, by coupling immunomagnetic bead sorting and exosomal sequencing, we found that exosome-derived circRNAs enriched in liver cancer CSCs were the key subsets with stemness characteristics and ultimately promoted HCC development. Of interest, we found that circ-ZEB1 and circ-AFAP1 are strongly correlated with liver cancer stemness and a poor prognosis, and can regulate the epithelial-mesenchymal transition (EMT) process. Our novel exosome-derived circRNAs play a vital role as key components of various intercellular crosstalk and communication systems in malignant transmission. This finding not only provides valuable support for utilizing plasma exosomal circRNAs as clinical prognostic indicators for HCC patients but also highlights a new research direction in exploring the signaling between liver CSCs and the messenger molecules contained within exosomes.