RAB27A‐dependent release of exosomes by liver cancer stem cells induces Nanog expression in their differentiated progenies and confers regorafenib resistance

• DOI: 10.1111/jgh.15619
• Publication Date: 2021-07-14T08:41:31Z
• Authors: Hongxia Huang; Jue Hou; Kewei Liu; Qin Liu; Liting Shen; Biying Liu; Qian Lu; Ni Zhang; Linrong Che; Jinyang Li; Shan Jiang; Bin Wang; Qinglian Wen; Lu Hu; Jian Gao
• Keywords: Homeobox protein NANOG; Regorafenib; Exosome

Regorafenib is a potent multikinase inhibitor for the second-line targeted therapy against hepatocellular carcinoma (HCC); however, drug resistance emerging in clinical settings. Although cancer stem cells (CSCs) are considered as key determinate of sensitivity, it remains unclear how CSCs may communicate with differentiated counterparts (non-CSC) to dictate therapeutic efficacy. Therefore, we sought investigate regorafenib mechanism HCC.We used sphere formation and soft agar colony assays evaluate stemness capacity cells. Cell viability assay was performed detect sensitivity regorafenib. Real-time quantitative polymerase chain reaction western blot were analyze gene expression. Mouse xenograft tumor model assess vivo.Exosomes highly enriched CSC supernatant compared that non-CSC, RAB27A mediates exosome secretion from maintain stem-like phenotype insensitivity. Moreover, exosomes released by upregulate expression Nanog while depleting sensitizes non-CSC presence exosomes. Consistently, analysis TCGA datasets reveals tightly correlates HCC tissues. More importantly, depletion downregulates nude mice.Our findings suggest release RAB27A-dependent manner induce cells, targeting this signaling between distinct cellular subsets be potential strategy patients.