Crocetin suppresses angiogenesis and metastasis through inhibiting sonic hedgehog signaling pathway in gastric cancer
Crocetin suppresses angiogenesis and metastasis through inhibiting sonic hedgehog signaling pathway in gastric cancer
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藏红花酸通过抑制胃癌中的sonic hedgehog信号通路抑制血管生成和转移
DOI：
10.1016/j.bbrc.2021.08.092
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发表时间：
2021-09-02
影响因子：
3.1
通讯作者：
Zhou, Ye
中科院分区：
文献类型：
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作者：
Zang, Mingde;Hou, Junyi;Zhou, Ye
胃癌（GC）是癌症相关死亡的主要原因之一，化疗耐药性是GC治疗的关键障碍，特别是在晚期GC中。西红花酸作为藏红花柱头的活性成分，对包括肿瘤在内的多种疾病具有重要的治疗作用。然而，西红花酸靶向GC的治疗潜力仍不清楚，其潜在机制仍有待进一步探讨。在这项研究中，西红花酸显着抑制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。西红花酸还抑制细胞增殖、迁移和侵袭。为了探索西红花酸参与的信号通路，我们检测了西红花酸处理后的HIF-1 α、Notch 1、Sonic hedgehog（SHH）和VEGF，发现SHH显著降低。西红花酸抑制SHH信号转导，蛋白质印迹分析显示SHH、PTCH 2、Sufu和Gli 1蛋白水平降低。此外，西红花酸抑制GC和HUVEC细胞分泌SHH。西红花酸在GC和HUVEC细胞共培养体系中也能抑制分泌型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，这些促进作用被西红花酸处理逆转。这些结果表明西红花酸通过SHH信号通路抑制胃癌的血管生成和转移，表明西红花酸可能是一种有效的抗胃癌药物。(C)2021爱思唯尔公司All rights reserved.
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-1 alpha, 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. (C) 2021 Elsevier Inc. All rights reserved.