MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1
MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1
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DOI：
10.1517/14728222.2015.1057569
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发表时间：
2015-08-01
影响因子：
5.8
通讯作者：
D'Angelo, Daniela
中科院分区：
文献类型：
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作者：
Mussnich, Paula;Rosa, Roberta;D'Angelo, Daniela
目的：我们的目的是分析差异表达的miRNA在结肠癌细胞中，以确定新的潜在的生物标志物参与癌细胞resistance.Design和方法：我们调查了miRNA表达谱的GEO人结肠癌细胞，敏感的EGFR抑制剂西妥昔单抗（CTX）和他们的CTX耐药对应物（GEO CR）通过使用miRNA芯片。我们发现，与GEO细胞相比，GEO CR中有27个上调和10个下调的miRNA，其倍数变化>= 2。在上调的miRNAs中，我们重点关注miR-199 a-5 p和miR-375。我们报告说，他们的强制表达促进CTX耐药性，而他们的沉默敏感相同的药物。miR-199 a-5 p和miR-375靶向PHLPP 1（PH结构域和富含亮氨酸的重复蛋白磷酸酶1）（一种负调节AKT途径的肿瘤抑制因子）的能力至少部分地解释了它们的耐药性活性。结论：miR-199 a-5 p和miR-375可能是导致结肠癌细胞对CTX耐药的重要因素之一，并为进一步研究miR-199 a-5 p和miR-375在结肠癌治疗中的作用提供了新的思路。
Objectives: We aimed to analyze the differentially-expressed miRNAs in colon cancer cells in order to identify novel potential biomarkers involved in cancer cell resistance.Design and methods: We investigated the miRNA expression profile of GEO human colon carcinoma cells, sensitive to the EGFR inhibitor Cetuximab (CTX) and their CTX-resistant counterpart (GEO CR) by using a miRNA chip.Results: We found 27 upregulated and 10 downregulated miRNAs in GEO CR compared with GEO cells with a fold change >= 2. Among the upregulated miRNAs, we focused on miR-199a-5p and miR-375. We report that their enforced expression promotes CTX resistance, whereas their silencing sensitizes to the same drug. The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AKT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of nniR-199a-5p and miR-375.Conclusion: This study proposes miR-199a-5p and miR-375 as contributors to CTX resistance in colon cancer and suggests a novel approach based on miRNAs as tools for the therapy of this tumor.