The reorganization of the cell cytoskeleton and changes in the content of cell adhesion molecules are crucial during the metastatic spread of tumor cells. Colorectal cancer (CRC) cells express high SMAD7, a protein involved in the control of CRC cell growth. In the present study, we evaluated whether SMAD7 regulates the cytoskeleton reorganization and dynamics in CRC. Knockdown of SMAD7 with a specific antisense oligonucleotide (AS) in HCT116 and DLD1, two human CRC cell lines, reduced the migration rate and the content of F-ACTIN filaments. A gene array, real-time PCR, and Western blotting of SMAD7 AS-treated cells showed a marked down-regulation of the X-linked inhibitor of apoptosis protein (XIAP), a member of the inhibitor of apoptosis family, which has been implicated in cancer cell migration. IL-6 and IL-22, two cytokines that activate STAT3, enhanced XIAP in cancer cells, and such induction was attenuated in SMAD7-deficient cells. Finally, in human CRC,SMAD7mRNA correlated withXIAPexpression. Our data show thatSMAD7positively regulatesXIAPexpression and migration of CRC cells, and suggest a mechanism by which SMAD7 controls the architecture components of the CRC cell cytoskeleton.
细胞骨架的重组与细胞黏附分子含量的变化在肿瘤细胞转移扩散过程中至关重要。结直肠癌细胞高表达SMAD7蛋白，该蛋白参与调控结直肠癌细胞生长。本研究旨在评估SMAD7是否调控结直肠癌细胞的骨架重组与动态变化。通过特异性反义寡核苷酸在人结直肠癌细胞系HCT116和DLD1中敲低SMAD7表达后，细胞迁移速率与F-肌动蛋白丝含量均显著降低。基因芯片分析、实时荧光定量PCR及蛋白质印迹实验显示，经SMAD7反义寡核苷酸处理的细胞中，X连锁凋亡抑制蛋白表达显著下调——该凋亡抑制家族成员已被证实参与癌细胞迁移过程。能够激活STAT3信号通路的细胞因子IL-6与IL-22可增强癌细胞中XIAP表达，而这种诱导效应在SMAD7缺陷细胞中被削弱。最后，在人结直肠癌组织中，SMAD7 mRNA表达水平与XIAP表达呈正相关。本研究数据表明，SMAD7正向调控XIAP表达及结直肠癌细胞迁移，并揭示了SMAD7调控结直肠癌细胞骨架结构成分的作用机制。
SMAD7 Sustains XIAP Expression and Migration of Colorectal Carcinoma Cells
肿瘤(癌症)患者之家