Exosomal linc00152 intensifies the crosstalk between cholangiocarcinoma cells and cancer-associated fibroblasts.

Abstract

Introduction and objectives: Cholangiocarcinoma is a highly lethal carcinoma. Exosomes derived from cancer-associated fibroblasts (CAFs) serve key roles in the crosstalk between CAFs and cancer cells. Exploring the roles of CAF-derived exosomes and the mechanisms contribute to a better understanding of the development of cholangiocarcinoma.

Materials and methods: Carcinoma and para-carcinoma tissues were collected from patients. Exosomes were isolated from CAFs and characterized by transmission electron microscopy, dynamic light scattering and western blot. Cholangiocarcinoma cells were cocultured with CAF-derived exosomes, and its proliferation, migration and invasion were evaluated with CCK-8, EdU incorporation and transwell assays, respectively. The interaction between a long non-coding RNA linc00152 and an RNA-binding protein hnRNPA2B1 was determined with RNA immunoprecipitation and RNA pull-down. The ubiquitination of hnRNPA2B1 was examined with western blot.

Results: Linc00152 was highly expressed in cholangiocarcinoma tissues and cells, and its increased expression was associated with advanced tumor stage and poor prognosis. Linc00152 was highly enriched in CAFs and CAF-derived exosomes. CAF-derived exosomes promoted cholangiocarcinoma cell proliferation, migration, and invasion by delivering linc00152. Further analysis showed that hnRNPA2B1 recruited linc00152 and enhanced its loading into exosomes. The interaction between hnRNPA2B1 and linc00152 was identified, and linc00152 repressed the proteasome-dependent degradation of hnRNPA2B1 in cholangiocarcinoma cells. The oncogenic activities of linc00152 in cholangiocarcinoma cells were dependent on hnRNPA2B1 upregulation.

Conclusions: CAF-derived exosomes harboring linc00152 enhance malignancy in cholangiocarcinoma, identifying a novel role of exosomal linc00152 for intensifying the crosstalk between CAFs and cholangiocarcinoma cells.