Kruppel-like factor 2 mediated anti-proliferative and anti-metastasis effects of simvastatin in p53 mutant colon cancer
Kruppel-like factor 2 mediated anti-proliferative and anti-metastasis effects of simvastatin in p53 mutant colon cancer
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Kruppel 样因子 2 介导辛伐他汀对 p53 突变结肠癌的抗增殖和抗转移作用
DOI：
10.1016/j.bbrc.2019.02.127
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发表时间：
2019-04-16
影响因子：
3.1
通讯作者：
Li, Mingxing
中科院分区：
文献类型：
--
作者：
Lu, Lan;Huang, Wenqing;Li, Mingxing
细胞代谢的变化在促进肿瘤进展中发挥着重要作用。最近的研究结果表明，抑癌基因p53的突变促进了脂质合成，并且突变型p53（mutp53）对于调节胆固醇合成的甲羟戊酸途径至关重要。辛伐他汀是一种3-羟基-3-甲基-戊二酰辅酶A（HMG-CoA）还原酶抑制剂，被发现对乳腺癌、结肠癌、肺癌等多种癌症具有治疗作用。然而，辛伐他汀抗肿瘤作用的潜在机制仍需进一步研究。我们的数据表明，辛伐他汀抑制甲羟戊酸途径显着上调突变型 p53 结肠癌细胞 SW1116 中的 Kruppel 样因子 2 (KLF2) 和 p21(WAF1)(/CIP1) 表达，但在 p53 野生型细胞 HCT116 中则不然。同时，我们发现KLF2的过表达可以显着诱导p21（WAF1）（/CIP1）表达，抑制Wnt信号传导并抑制上皮间质转化，表明KL2可能介导辛伐他汀在SW1116细胞中的抗肿瘤作用。此外，癌症基因组图谱（TCGA）数据库的生物信息分析表明，KLF2与CDKN1A（编码p21（WAF1）（/CIP1））呈正相关，两者在结肠癌组织中，特别是在p53突变的结肠癌组织中均下调。结果表明KLF2可能是结肠癌的抑癌基因，这与我们的实验数据一致。我们还发现，与p53野生型结肠癌组织相比，突变型p53结肠癌组织中CDKNIA的表达显着降低，而Wnt配体Wnt5a在p53突变型结肠癌组织中表现出最高水平。这些数据为辛伐他汀治疗p53突变结肠癌的临床应用提供了有力的证据。 (C) 2019 Elsevier Inc. 保留所有权利。
The changes in cellular metabolism play an important role in promoting tumor progression. Recent findings suggested that the mutation of tumor suppressor gene p53 promoted lipids synthesis and mutant p53 (mutp53) was essential for regulating mevalonate pathway for cholesterol synthesis. Simvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, was found to exhibit therapeutic effects against many types of cancers including breast cancer, colon cancer, lung cancer, etc. However, the underlying mechanism of the antitumor effect of simvastatin still needs to be further investigated. Our data demonstrated that suppression of mevalonate pathway by simvastatin significantly upregulated Kruppel-like factor 2 (KLF2) and p21(WAF1)(/CIP1) expression in mutant p53 colon cancer cells SW1116 but not in p53 wild type cells HCT116. Meanwhile, we found that overexpression of KLF2 could significantly induce p21(WAF1)(/CIP1) expression, inhibit Wnt signaling and suppress epithelialmesenchymal transition, indicating that KL2 might mediate antitumor effect of simvastatin in SW1116 cells. Moreover, bioinformatic analysis from The Cancer Genome Atlas (TCGA) database indicated that KLF2 were positively correlated with CDKN1A (encoding p21(WAF1)(/CIP1)), both of which were down-regulated in colon cancer tissue, especially in p53 mutant colon cancer tissue. The results showed that KLF2 might be a tumor suppressor gene in colon cancer, which was in accordance with our experimental data. We also found that CDKNIA expression in mutant p53 colon cancer tissue was significant decreased when compared with p53 wild type colon cancer tissue, while Wnt ligand Wnt5a exhibited the highest level in p53 mutant colon cancer tissue. These data provide strong evidences for clinical application of simvastatin in treatment of colon cancer with p53 mutation. (C) 2019 Elsevier Inc. All rights reserved.