Gastric cancer (GC) is one of the major causes of cancer-related deaths and chemoresistance is a key obstacle to the treatment of GC, particularly in advanced GC. As an active component of saffron stigma, crocetin has important therapeutic effects on various diseases including tumors. However, the therapeutic potential of crocetin targeting GC is still unclear and the underlying mechanisms are remained to be further explored. In this study, crocetin significantly inhibited angiogenesis in GC, including tubes of HUVECs and vasculogenic mimicry (VM) formation of GC cells. Crocetin also suppressed cell proliferation, migration and invasion. To explore which signaling pathway involving in crocetin, HIF-1α, Notch1, Sonic hedgehog (SHH) and VEGF were examined with crocetin treatment and we found that SHH significantly decreased. Crocetin suppressed SHH signaling with SHH, PTCH2, Sufu and Gli1 protein level decreased in western blot assay. In addition, crocetin suppressed SHH secretion in GC and HUVEC cells. The promoted effects on cell migration induced by secreted SHH were also inhibited by crocetin in GC and HUVEC cell co-culture system. Furthermore, recombinant SHH promoted angiogenesis as well as cell migration and proliferation. However, these promoted effects were reversed by crocetin treatment. These results revealed that crocetin suppressed GC angiogenesis and metastasis through SHH signaling pathway, indicating that crocetin may function as an effective therapeutic drug against GC.

胃癌 (GC) 是癌症相关死亡的主要原因之一，化学耐药性是治疗 GC，尤其是晚期 GC 的主要障碍。作为藏红花柱头的活性成分，藏红花素对包括肿瘤在内的多种疾病具有重要的治疗作用。然而，藏红花素靶向 GC 的治疗潜力仍不清楚，其潜在机制仍有待进一步探索。在这项研究中，藏红花素显着抑制 GC 中的血管生成，包括 HUVEC 管和 GC 细胞的血管生成拟态 (VM) 形成。藏红花素还抑制细胞增殖、迁移和侵袭。为了探索藏红花素中涉及哪条信号通路，用藏红花素处理检查了 HIF-1α、Notch1、Sonic Hedgehog (SHH) 和 VEGF，我们发现 SHH 显着降低。藏红花素抑制 SHH 信号传导，在蛋白质印迹试验中，SHH、PTCH2、Sufu 和 Gli1 蛋白水平降低。此外，藏红花素抑制 GC 和 HUVEC 细胞中的 SHH 分泌。GC 和 HUVEC 细胞共培养系统中的藏红花素也抑制了分泌型 SHH 对细胞迁移的促进作用。此外，重组 SHH 促进血管生成以及细胞迁移和增殖。然而，这些促进作用被藏红花素处理逆转。这些结果表明，藏红花素通过 SHH 信号通路抑制 GC 血管生成和转移，表明藏红花素可能是一种有效的 GC 治疗药物。GC 和 HUVEC 细胞共培养系统中的藏红花素也抑制了分泌型 SHH 对细胞迁移的促进作用。此外，重组 SHH 促进血管生成以及细胞迁移和增殖。然而，这些促进作用被藏红花素处理逆转。这些结果表明，藏红花素通过 SHH 信号通路抑制 GC 血管生成和转移，表明藏红花素可能是一种有效的 GC 治疗药物。GC 和 HUVEC 细胞共培养系统中的藏红花素也抑制了分泌型 SHH 对细胞迁移的促进作用。此外，重组 SHH 促进血管生成以及细胞迁移和增殖。然而，这些促进作用被藏红花素处理逆转。这些结果表明，藏红花素通过 SHH 信号通路抑制 GC 血管生成和转移，表明藏红花素可能是一种有效的 GC 治疗药物。