Exosome‐mediated miR‐4660 delivery inhibits OPN promoted hepatoma cells aggression through targeting LGALS3BP

Abstract Hepatocellular carcinoma (HCC) is an aggressive malignant tumor with poor prognosis due to its strong metastatic potential. Studies linked osteopontin (OPN) to increased HCC metastasis. However, the mechanisms, especially those involving exosomes, are not well elucidated. This study investigates how OPN influences HCC cells behavior via exosome mediation. A stable HCC cell line overexpressing OPN, named SMMC‐OPN, was established. Co‐culture experiment revealed that exosomes from SMMC‐OPN cells enhanced the migration and invasion of the parental SMMC‐7721 cells. RNA sequencing found the downregulation of miR‐4660 in these exosomes, which targets LGALS3BP (galectin‐3 binding protein), elevated in both SMMC‐OPN cells and their exosomes. Treatment with SMMC‐OPN exosomes resulted in an upregulation of LGALS3BP expression in SMMC‐7721 cells. Notably, upon forced overexpression of miR‐4660 in SMMC‐OPN cells, miR‐4660 was observed to be encapsulated in exosomes. Co‐culture experiments demonstrated that exosomes containing miR‐4660, derived from miR‐4660‐overexpressing SMMC‐OPN cells, counter‐acted the promigratory and invasive effects of SMMC‐OPN exosomes on recipient SMMC‐7721 cells. These findings suggest that the downregulation of miR‐4660 in SMMC‐OPN exosomes contributes to the enhanced metastatic potential of HCC through modulating LGALS3BP. Furthermore, miR‐4660 delivery via exosomes inhibits OPN‐promoted hepatoma cell aggression by targeting LGALS3BP, highlighting a potential therapeutic target against cancer metastasis.