sEV-mediated intercellular transformation from MGAT4AHigh to MGAT4ALow tumor cells via the HOTAIRM1/miR-196b-5p axis promotes apoptosis resistance in CTCL.

Abstract

ncRNAs encapsulated in small extracellular vesicles (sEVs) facilitate intercellular communication and are associated with tumor progression. lncRNA-HOTAIRM1 is aberrantly expressed in various cancers. However, HOTAIRM1 expression and its downstream ceRNA network in CTCL remains unclear. In this study, we found that HOTAIRM1 was reduced in CTCL. Elevated HOTAIRM1 inhibited proliferation and induced apoptosis in vitro, resulting in reduced in vivo tumorigenic capacity. Whole-transcriptome sequencing and scRNA-Seq confirmed that differential expression of HOTAIRM1/miR-196b-5p/MGAT4A axis induces apoptosis resistance in CTCL. Mechanistically, reduced MGAT4A expression in CTCL leads to decreased N-glycosylation modification of membrane proteins and reduced Galectin-1 affinity, thereby inducing partial resistance to Galectin-1-induced apoptosis. Meanwhile, benign CD4 + T cells show sensitivity to Galectin-1-induced apoptosis due to their relatively higher MGAT4A expression. Furthermore, MGAT4A^Low CTCL tumor cells transformed MGAT4A^High CD4+ benign cells into MGAT4A^Low cells by secreting sEVs containing miR-196b-5p, thereby reducing Galectin-1 binding and inducing apoptosis resistance. Engineered sEVs from HOTAIRM1-overexpressing cells contain elevated HOTAIRM1, which can specifically target malignant T cells, with reduced miR-196b-5p and increased MGAT4A, demonstrating apoptosis-inducing and tumor-suppressive effects in CTCL. This study identified changes in HOTAIRM1/miR-196b-5p/MGAT4A axis and N-glycosylation modifications in CTCL. Engineered HOTAIRM1-loaded sEVs demonstrated promising targeting and therapeutic effects in CTCL.