【科技前瞻】Cancer Letters：外泌体靶向胃癌分子机制或可有助于开发胃癌诊断新方法

胃癌（GC）是全球第五大常见的恶性肿瘤，也是癌症死亡的第三大原因。由于缺乏明确的诊断分子生物标志物，胃癌通常在发现时就已经被诊断为晚期，并且5年生存率只有20-30％。通常导致胃癌的发展和进展的因素有遗传、表观遗传和环境因素。近期，研究人员新发现一种miRNA，可以通过外泌体进行传播，并且外泌体通过miR-501靶向对胃癌的化疗耐药性和肿瘤发生起到了促进作用。相关研究结果发表在Cancer Letters杂志上。

致癌miRNAs的体外转移可以增强受体细胞的生长、转移和化学抗性。研究人员发现microRNA-501-5p (miR-501)在抗阿霉素胃癌细胞分泌的外泌体(ADR Exo)中比正常细胞分泌的外泌体显著高表达。ADR Exo增强了胃癌细胞对多柔比星的耐药性、增殖能力、迁移和侵袭能力，并抑制细胞凋亡。敲低miR-501或过表达BLID可以逆转ADR Exo对受体细胞的不良影响。用外泌体抑制剂GW4869处理与SGC7901 / ADR共培养的SGC7901细胞，或者在细胞中转染miR-501抑制剂，可以使细胞恢复对多柔比星的敏感性并且表现出增殖、迁移和侵袭能力减弱以及细胞凋亡增加。与miR-501敲低或BLID过表达的细胞相比，瘤内注射ADR Exo至对照组SGC7901细胞后，皮下肿瘤生长速度加快并且出现对多柔比星的耐药性。综上所述，这些效应可能通过外泌体miR-501诱导的BLID下调，随后通过caspase-9 / -3的失活和Akt的磷酸化激活来实现的。因此研究人员认为，外泌体miR-501可能是胃癌的新的治疗靶点。

推荐阅读原文：

Exosomal transfer of miR-501 confers doxorubicin resistance and tumorigenesis via targeting of BLID in gastric cancer.

Exosomal transfer of oncogenic miRNAs can enhance recipient cell growth, metastasis and chemoresistance. Currently we found that microRNA-501-5p (miR-501) was overexpressed in doxorubicin-resistant gastric cancer (GC) SGC7901/ADR cell-secreted exosomes (ADR Exo) than that in SGC7901 cell-secreted exosomes (7901 Exo). ADR Exo was internalized by SGC7901, and a Cy3-miR-501 mimic was transferred from SGC7901/ADR to SGC7901 via exosomes. ADR Exo conferred doxorubicin resistance, proliferation, migration and invasion abilities to negative control miRNA inhibitor-expressing GC cells, whereas it inhibited apoptosis. MiR-501 knockdown or BH3-like motif-containing protein, cell death inducer (BLID) overexpression could reverse the effects of ADR Exo on recipient cells. SGC7901 cells cocultured with SGC7901/ADR prior to treatment with GW4869 or transfection of a miR-501 inhibitor were sensitive to doxorubicin and exhibited attenuated proliferation, migration and invasion and increased apoptosis. The intratumoral injection of ADR Exo into negative control miRNA inhibitor-expressing SGC7901?cells induced rapid subcutaneous tumor growth and resistance to doxorubicin compared to that of miR-501 knockdown or BLID-overexpressing cells. This effect is possibly achieved by exosomal miR-501-induced downregulation of BLID, subsequent inactivation of caspase-9/-3 and phosphorylation of Akt. Exosomal miR-501 might be a therapeutic target for GC.

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