Inhibition of Tcf-4 induces apoptosis and enhances chemosensitivity of colon cancer cells.
Inhibition of Tcf-4 induces apoptosis and enhances chemosensitivity of colon cancer cells.
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DOI：
10.1371/journal.pone.0045617
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wang XL
中科院分区：
文献类型：
--
作者：
Xie J;Xiang DB;Wang H;Zhao C;Chen J;Xiong F;Li TY;Wang XL
β-catenin/Tcf-4信号传导的异常激活与人类致癌作用有关，包括结直肠癌。在这项研究中，我们比较了Tcf-4基因敲低和β-catenin基因敲低对细胞增殖，凋亡和化疗敏感性的影响，在SW 480和HCT 116结肠癌细胞使用腺病毒载体介导的短发夹RNA（shRNA）。我们的研究结果表明，与β-catenin敲低相比，Tcf-4敲低更有效地抑制结肠癌细胞的集落形成，诱导凋亡，并增加5-FU和奥沙利铂介导的细胞毒性。我们进一步研究了β-连环蛋白和Tcf-4敲低在结肠癌细胞中观察到的不同功效所涉及的机制。FOXO 4是哺乳动物FOXO叉头转录因子亚家族的成员，在控制细胞增殖、凋亡和DNA修复中起主要作用。我们的数据显示，FOXO 4的蛋白水平在β-catenin和Tcf-4 shRNA处理后没有改变。而β-catenin shRNA可增加磷酸化FOXO 4 S193的积累，降低FOXO靶基因p27 Kip 1和MnSOD的表达，而Tcf-4 shRNA则表现出相反的作用。因此，与β-catenin敲低相比，Tcf-4敲低显示出更好的抑制结直肠癌细胞增殖和诱导凋亡的功效，这可能与FOXO 4转录活性增加有关。这些结果表明，Tcf-4是一个有吸引力的潜在的治疗靶点，用于结直肠癌的治疗。
Aberrant activation of β-catenin/Tcf-4 signaling has been implicated in human carcinogenesis, including colorectal cancer. In this study, we compared the effects of Tcf-4 knockdown with β-catenin knockdown on cell proliferation, apoptosis, and chemosensitivity in SW480 and HCT116 colon cancer cells using adenoviral vector-mediated short hairpin RNA (shRNA). Our results show that, compared to β-catenin knockdown, Tcf-4 knockdown more effectively inhibited colony formation, induced apoptosis, and increased 5-FU and oxaliplatin-mediated cytotoxicity in colon cancer cells. We further investigated the mechanisms involved in the different efficacies observed with β-catenin and Tcf-4 knockdown in colon cancer cells. FOXO4 is a member of the subfamily of mammalian FOXO forkhead transcription factors and plays a major role in controlling cellular proliferation, apoptosis, and DNA repair. Our data showed that the protein level of FOXO4 did not change after treatment with both β-catenin and Tcf-4 shRNA. However, β-catenin shRNA was found to increase the accumulation of phosphorylated FOXO4 S193 and decrease the expression of FOXO target genes p27Kip1 and MnSOD, whereas Tcf-4 shRNA showed the opposite effect. Therefore, compared to β-catenin knockdown, Tcf-4 knockdown shows better efficacy for inhibiting proliferation and inducing apoptosis of colorectal cancer cells, which may be related to increased FOXO4 transcriptional activity. These results suggest that Tcf-4 is an attractive potential therapeutic target for colorectal cancer therapy.
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