Zang Mingde, Hou Junyi, Huang Yakai, Wang Jiangli, Ding Xusheng, Zhang Baogui, Wang Yanong, Xuan Yi, Zhou Ye
Department of Gastric Cancer Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China.
Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, PR China.
Biochem Biophys Res Commun. 2021 Oct 22;576:86-92. doi: 10.1016/j.bbrc.2021.08.092. Epub 2021 Aug 31.
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，化疗耐药是GC治疗的关键障碍，尤其是在晚期GC中。作为藏红花柱头的活性成分，西红花酸对包括肿瘤在内的各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，其潜在机制有待进一步探索。在本研究中，西红花酸显著抑制GC中的血管生成，包括人脐静脉内皮细胞（HUVECs）的血管形成和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。为了探究西红花酸涉及哪些信号通路，在用西红花酸处理后检测了缺氧诱导因子-1α（HIF-1α）、Notch1、音猬因子（SHH）和血管内皮生长因子（VEGF），发现SHH显著降低。在蛋白质印迹分析中，西红花酸抑制SHH信号通路，SHH、patched受体2（PTCH2）、肿瘤抑制因子（Sufu）和glioma相关癌基因家族锌指蛋白1（Gli1）蛋白水平降低。此外，西红花酸抑制GC和HUVEC细胞中SHH的分泌。在GC和HUVEC细胞共培养系统中，西红花酸也抑制了分泌型SHH诱导的细胞迁移促进作用。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所逆转。这些结果表明，西红花酸通过SHH信号通路抑制GC血管生成和转移，表明西红花酸可能作为一种有效的抗GC治疗药物发挥作用。
