Microvesicles mediate sorafenib resistance in liver cancer cells through attenuating p53 and enhancing FOXM1 expression

Drug resistance in cancer, still poses therapeutic challenges and tumor microenvironment plays a critical role in it. Microvesicles (MVs) are effective transporters of the molecular information between cells and regulate the tumor microenvironment. They contribute to the drug resistance by transferring functional molecules between cells. Herein we report the effects of liver cancer cell-secreted MVs on sorafenib resistance in liver cancer cells HepG2 and Huh7 both in vitro and in vivo. In our study, these cancer cell-secreted MVs affected the anti-proliferative effect of sorafenib in a dose- and time-dependent manner and also inhibited the sorafenib induced apoptosis in vitro. Further, in in-vivo xenograft mice models, liver cancer cell-secreted MVs increased the tumor volume even after sorafenib treatment. Further, HGF, also got elevated in liver cancer cell-secreted MVs treatment group and activated Ras protein expression. miR-25 in the cancer cell-secreted MVs was transferred to their host cells HepG2 and Huh7 cells and reversed the sorafenib induced expression of tumor suppressor p53. This in turn induced the expression of FOXM1, a key regulator of cell cycle progression and thus affected the anti-proliferative effect of sorafenib. Therefore, this study reveals that liver cancer cell-derived MVs can mediate sorafenib resistance in the liver cancer cells, suggesting that these MVs may not be utilized as vehicles for anti-cancer drug delivery in liver cancer treatments.

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