Abstract：
Gastric cancer is one of the deadliest malignant tumors, and half of the patients develop recurrences or metastasis within 5 years after eradication therapy. Cancer stem cells (CSCs) are considered to be important in this progress. The sonic hedgehog (SHH) pathway plays an important role in the maintenance of gastric CSCs characteristics. The p63 proteins are vital transcription factors belonging to the p53 family, while their functions in regulating CSCs remain unclear. The preventive effects of dietary diallyl trisulfide (DATS) against human gastric cancer have been verified. However, whether DATS can target gastric CSCs are poorly understood. Here, we investigated the role of ΔNp63/SHH pathway in gastric CSCs and the inhibitory effect of DATS on gastric CSCs via ΔNp63/SHH pathway. We found that ΔNp63 was upregulated in serum-free medium cultured gastric tumorspheres compared with the parental cells. Overexpression of ΔNp63 elevated the self-renewal capacity and CSC markers\' levels in gastric sphere-forming cells. Furthermore, we found that ΔNp63 directly bound to the promoter region of Gli1, the key transcriptional factor of SHH pathway, to enhance its expression and to activate SHH pathway. In addition, it was revealed that DATS effectively inhibited gastric CSC properties both in vitro and in vivo settings. Activation of SHH pathway attenuated the suppressive effects of DATS on the stemness of gastric cancer. Moreover, DATS suppression of gastric CSC properties was also diminished by ΔNp63 upregulation through SHH pathway activation. These findings illustrated the role of ΔNp63/SHH pathway in DATS inhibition of gastric cancer stemness. Taken together, the present study suggested for the first time that DATS inhibited gastric CSCs properties by ΔNp63/SHH pathway.
摘要：
胃癌是最致命的恶性肿瘤之一,一半的患者在根除治疗后5年内出现复发或转移。癌症干细胞（CSC）被认为在这一进程中很重要。Sonichedgehog（SHH）通路在维持胃CSCs特性中起着重要作用。p63蛋白是p53家族的重要转录因子，虽然它们在调节CSCs中的功能尚不清楚。膳食二烯丙基三硫化物（DATS）对人胃癌的预防作用已得到验证。然而,DATS是否可以靶向胃CSC尚不清楚。这里,我们研究了ΔNp63/SHH途径在胃CSC中的作用以及DATS通过ΔNp63/SHH途径对胃CSC的抑制作用。我们发现，与亲本细胞相比，无血清培养基培养的胃肿瘤球中的ΔNp63上调。ΔNp63的过表达提高了胃球体形成细胞中的自我更新能力和CSC标记物的水平。此外，我们发现ΔNp63与SHH通路的关键转录因子Gli1的启动子区直接结合,增强其表达并激活SHH途径。此外,揭示了DATS在体外和体内设置中均有效抑制胃CSC特性。SHH通路的激活减弱了DATS对胃癌干性的抑制作用。此外，通过SHH途径激活的ΔNp63上调也减少了DATS对胃CSC特性的抑制。这些发现说明了ΔNp63/SHH途径在DATS抑制胃癌干性中的作用。一起来看,本研究首次表明DATS通过ΔNp63/SHH途径抑制胃CSCs的性质。
