International immunopharmacology · 2026
Keratinocyte-derived exosomal miR-31-5p reduces vemurafenib sensitivity in melanoma cells.
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Li Yan, Chen Qiyu, Zhang Qian, Miao Shuping, Lan Yufei, Ou Rongying, Tang Bo, Xu Yunsheng
Аннотация
BACKGROUND: Resistance to BRAFV600E inhibitors (e.g., vemurafenib) remains a major challenge in malignant melanoma treatment. Keratinocytes influence melanoma cell sensitivity to vemurafenib, but the role of keratinocyte-derived exosomes in melanoma cell sensitivity to vemurafenib remains unclear.
OBJECTIVE: In this study, we aimed to investigate the effects and mechanisms of keratinocyte-derived exosomes on melanoma cell growth and sensitivity to vemurafenib.
METHODS: Exosomes were extracted from HaCaT keratinocytes. The growth of melanoma cell line A375 and UACC62 was assessed in vitro and in vivo. miRNA profiles of HaCaT-derived exosomes were characterized using RNA sequencing. miR-31-5p, AlkB homolog 1 (ALKBH1), and RNA m6A levels in A375 and UACC62 cells were evaluated using qRT-PCR, Western blotting, and RNA immunoprecipitation (RIP) assays.
RESULTS: HaCaT-derived exosomes promoted melanoma cell growth and reduced their sensitivity to vemurafenib both in vitro and in vivo. Exosomes from vemurafenib-treated HaCaT cells had stronger effects. Vemurafenib treatment increased miR-31-5p levels in HaCaT-derived exosomes, which subsequently upregulated miR-31-5p in recipient melanoma cells. The miR-31-5p inhibitor and the m6A inhibitor cycloleucine blocked exosome-induced proliferation, increases in global m6A levels, and decreases in vemurafenib sensitivity. ALKBH1, a typical demethylase of nucleic acids, was a direct target of miR-31-5p. ALKBH1 overexpression reversed exosome- and miR-31-5p mimic-induced changes in ALKBH1 expression, m6A levels, proliferation, and vemurafenib sensitivity.
CONCLUSION: Vemurafenib increases miR-31-5p in keratinocyte-derived exosomes, which suppresses ALKBH1 and elevates RNA m6A in melanoma cells, thereby promoting proliferation and reducing vemurafenib sensitivity. Targeting the miR-31-5p/ALKBH1 axis and m6A modification may offer a potential therapeutic strategy to enhance vemurafenib sensitivity in BRAFV600E melanoma cells.
OBJECTIVE: In this study, we aimed to investigate the effects and mechanisms of keratinocyte-derived exosomes on melanoma cell growth and sensitivity to vemurafenib.
METHODS: Exosomes were extracted from HaCaT keratinocytes. The growth of melanoma cell line A375 and UACC62 was assessed in vitro and in vivo. miRNA profiles of HaCaT-derived exosomes were characterized using RNA sequencing. miR-31-5p, AlkB homolog 1 (ALKBH1), and RNA m6A levels in A375 and UACC62 cells were evaluated using qRT-PCR, Western blotting, and RNA immunoprecipitation (RIP) assays.
RESULTS: HaCaT-derived exosomes promoted melanoma cell growth and reduced their sensitivity to vemurafenib both in vitro and in vivo. Exosomes from vemurafenib-treated HaCaT cells had stronger effects. Vemurafenib treatment increased miR-31-5p levels in HaCaT-derived exosomes, which subsequently upregulated miR-31-5p in recipient melanoma cells. The miR-31-5p inhibitor and the m6A inhibitor cycloleucine blocked exosome-induced proliferation, increases in global m6A levels, and decreases in vemurafenib sensitivity. ALKBH1, a typical demethylase of nucleic acids, was a direct target of miR-31-5p. ALKBH1 overexpression reversed exosome- and miR-31-5p mimic-induced changes in ALKBH1 expression, m6A levels, proliferation, and vemurafenib sensitivity.
CONCLUSION: Vemurafenib increases miR-31-5p in keratinocyte-derived exosomes, which suppresses ALKBH1 and elevates RNA m6A in melanoma cells, thereby promoting proliferation and reducing vemurafenib sensitivity. Targeting the miR-31-5p/ALKBH1 axis and m6A modification may offer a potential therapeutic strategy to enhance vemurafenib sensitivity in BRAFV600E melanoma cells.