Long non-coding RNA H19 transported by colorectal cancer small extracellular vesicles promotes alternative splicing in healthy hepatocytes: new insights on liver pre-metastatic niche formation

Abstract

Colorectal cancer (CRC) is the second most lethal cancer and metastatic dissemination of CRC cells, which predominantly occurs to the liver, is the principal cause of death. Many studies have highlighted the role of CRC-derived small extracellular vesicles (CRC-sEVs) in priming the pre-metastatic niche (PMN) in the liver, promoting morpho-functional alterations which pave the way for the establishment of a favourable microenvironment for future organ colonization by metastatic cells. Our research group demonstrated the effects of CRC-sEVs in promoting the epithelial-to-mesenchymal transition (EMT) of healthy human hepatocytes. In this study, we focused our attention on the long non-coding RNA H19 (lncH19), an oncogenic non-coding RNA whose role in CRC progression has been widely documented. Our data demonstrated that lncH19 is specifically loaded inside CRC-sEVs, carrying with it the RNA binding Fox-1 Homolog 2 (RBFOX2). The treatment of healthy human hepatocytes with CRC-sEVs allows the horizontal transfer of the complex that conveys a pro-EMT post-transcriptional modulation of RBFOX2 target genes.