BackgroundAccumulating evidence indicates that curcumin (CUR) has anticancer properties in various cancers including oral squamous cell carcinoma (OSCC), but CUR is greatly restricted in clinical studies and applications due to its low bioavailability. Interestingly, the bioavailability of CUR was found to be significantly improved using loaded lipid nanoemulsions (NEs).ObjectivesTo investigate the effect of CUR‐NEs on cell proliferation of OSCC HSC‐3 cells in vitro, and explore the potential mechanism of this effect in a preliminary study.ResultsCUR‐NEs exhibited significantly cytotoxic effects on OSCC cells in a dose‐dependent manner, compared with the control. The percentage of cells in proliferative phases (S + G2/M) was gradually decreased in a dose‐ or time‐dependent manner caused by CUR‐NEs. Moreover, CUR‐NEs downregulated the protein expression of PI3K/Akt/mTOR and upregulated the expression of miR‐199a that targeted PI3K in a dose‐ or time‐dependent manner in OSCC cells. Importantly, CUR‐NEs cloud effectively counteract the influence on cell proliferation of OSCC cells and the proliferative phases of cell cycle caused by miR‐199a inhibitor a time‐dependent manner.ConclusionsThis in vitro preliminary study indicated that CUR‐NEs may be an effective therapeutic agent for OSCC. Such effects could be related to inhibition of OSCC cell proliferation by PI3K/Akt/mTOR suppression and miR‐199a upregulation.

Cancer-derived small extracellular vesicles (sEVs) are emerging as crucial mediators of intercellular communication between cancer cells and M2-tumor-associated macrophages (M2-TAMs) via transferring lncRNAs. We previously reported that miR-134 blocks the expression of its targeting protein LAMC2 via the PI3K/AKT pathway and inhibits cancer stem cell (CSC) migration and invasion in oral squamous cell carcinoma (OSCC). This study hypothesize that OSCC-CSC-derived small extracellular vesicles (OSCC-CSC-sEVs) transfer a ceRNA of miR-134 and consequently promote M2 macrophage polarization by targeting LAMC2 via the PI3K/AKT pathway through in vitro and in vivo experiment methods. The results showed that sEVs derived from CD133+CD44+ OSCC cells promoted M2 polarization of macrophages by detecting several M2 macrophage markers (CD163, IL-10, Arg-1, and CD206+CD11b+). Mechanistically, we revealed that the lncRNA UCA1, by binding to miR-134, modulated the PI3K/AKT pathway in macrophages via targeting LAMC2. Importantly, OSCC-CSC-sEV transfer of UCA1, by targeting LAMC2, promoted M2 macrophage polarization and inhibited CD4+ T-cell proliferation and IFN-γ production in vitro and in vivo. Functionally, we demonstrated that M2-TAMs, by transferring exosomal UCA and consequently targeting LAMC2, enhanced cell migration and invasion of OSCC in vitro and the tumorigenicity of OSCC xenograft in nude mice. In conclusion, our results indicated that OSCC-CSC-sEV transfer of UCA1 promotes M2 macrophage polarization via a LAMC2-mediated PI3K/AKT axis, thus facilitating tumor progression and immunosuppression. Our findings provide a new understanding of OSCC-CSC molecular mechanisms and suggest a potential therapeutic strategy for OSCC through targeting CSC-sEVs and M2-TAMs.