Snail Contributes to the Maintenance of Stem Cell-Like Phenotype Cells in Human Pancreatic Cancer

Snail, a potent repressor of E-cadherin expression, plays a key role in epithelial-to-mesenchymal transition (EMT) in epithelial cancer. Recently, EMT and stemness programs are found linked together. In the current study, the expression of Snail and its contribution to cancer stem cell (CSC) marker expression, invasiveness, self-renewal, clonogenicity, and tumorigenicity of pancreatic cancer cells were studied. Our results showed that Snail was highly expressed in CSChigh cell line Panc-1. Stable, short hairpin RNA (shRNA)-mediated Snail knockdown decreased invasion in Panc-1 cells, in line with increased E-cadherin expression and its translocation from the nucleus to the membrane. Snail silencing in Panc-1 also inhibited CSC marker ALDH expression, together with decreased sphere and colony forming capacity, which was highly consistent with the expression of stem cell associated transcription factors like Sox2 and Oct4. In mouse xenograft models, knockdown of Snail led to a reduced number of tumor-bearing mice and a reduced average size of tumors, which had a stronger membrane staining of E-cadherin and lighter staining of Oct4. Collectively, these findings implicate Snail is required for the maintenance of stem cell-like phenotype in pancreatic cancer, and inhibition of Snail could be an efficient strategy to treat pancreatic cancer by targeting CSCs.Snail（一种强效的上皮钙黏蛋白（E-cadherin）表达抑制因子）在上皮性癌症的上皮间质转化（epithelial-to-mesenchymal transition, EMT）过程中发挥关键作用。近期研究发现，EMT与干细胞干性程序存在紧密关联。本研究探究了Snail的表达情况，及其对胰腺癌细胞的癌症干细胞（cancer stem cell, CSC）标志物表达、侵袭能力、自我更新能力、克隆形成能力及致瘤性的影响。研究结果显示，Snail在CSC高表达胰腺癌细胞系Panc-1中呈高表达状态。通过稳定表达短发夹RNA（short hairpin RNA, shRNA）介导敲低Snail后，Panc-1细胞的侵袭能力下降，这与E-钙黏蛋白表达上调及其从细胞核向细胞膜的转位相一致。在Panc-1细胞中沉默Snail还可抑制癌症干细胞标志物乙醛脱氢酶（ALDH）的表达，同时降低细胞成球及克隆形成能力，这与Sox2、Oct4等干细胞相关转录因子的表达下调高度一致。在小鼠异种移植模型中，敲低Snail可减少荷瘤小鼠数量并降低肿瘤平均体积，且该组肿瘤的E-钙黏蛋白膜染色更强、Oct4染色更弱。综上，上述研究结果表明，Snail是维持胰腺癌干细胞样表型所必需的，而靶向抑制Snail或可通过靶向癌症干细胞成为治疗胰腺癌的有效策略。