A panel of serum exosomal microRNAs as predictive markers for chemoresistance in advanced colorectal cancer
A panel of serum exosomal microRNAs as predictive markers for chemoresistance in advanced colorectal cancer
复制标题
一组血清外泌体 microRNA 作为晚期结直肠癌化疗耐药的预测标志物
DOI：
10.1007/s00280-019-03867-6
复制
发表时间：
2019-08-01
影响因子：
3
通讯作者：
Huang, Zhaohui
中科院分区：
文献类型：
--
作者：
Jin, Guoying;Liu, Yuhang;Huang, Zhaohui
背景化疗耐药是世界范围内肿瘤治疗的共同问题。循环外泌体microRNA（miRNAs）被认为是肿瘤的有前途的生物标志物。然而，很少有研究评估血清/血浆exosomal microRNAs与大肠癌（CRC）化疗耐药的关系。方法在以往基因芯片分析的基础上，我们选择了30个在大肠癌进展过程中异常表达的miRNAs，然后检测其在3对奥沙利铂/5-氟尿嘧啶耐药的大肠癌细胞系及其分泌的exosomal中的表达水平。鉴定了六种候选外泌体miRNA，以进一步评估预测晚期CRC患者化疗效果的潜在价值。最后，利用生物信息学方法对这些miRNAs在大肠癌耐药中的分子机制进行了初步探讨。在这些miRNA中，miR-21- 5 p、miR-1246、miR-1229- 5 p、miR-135 b、miR-425和miR-96- 5 p也在来自抗性细胞培养基的外来体中上调。临床样本分析证实，与化学敏感对照相比，血清外泌体中miR-21- 5 p、miR-1246、miR-1229- 5 p和miR-96- 5 p的表达水平在化学耐药患者中显著更高。ROC曲线显示，4种miRNAs组合的曲线下面积（AUC）为0.804（P< 0.05）。GO分析和KEGG通路分析显示，这些miRNAs在PI 3 K-Akt信号通路、FoxO信号通路和自噬通路中富集。结论一组血清外泌体miRNAs（miR-21- 5 p、miR-1246、miR-1229- 5 p和miR-96- 5 p）可显著区分化疗耐药组和晚期结直肠癌患者。靶向这些miRNAs可能会提高对奥沙利铂和5-氟尿嘧啶的化疗敏感性，并可能成为有希望的CRC治疗策略。
BackgroundChemoresistance is a common problem for cancer treatment worldwide. Circulating exosomal microRNAs (miRNAs) have been considered as promising biomarkers of cancers. However, few studies have assessed the relationship between serum/plasma exosomal microRNAs and chemoresistance in colorectal cancer (CRC).MethodsBased on previous microarray analysis, we selected 30 miRNAs which are aberrantly expressed during CRC progression and then detected their expression levels in three pairs of oxaliplatin/5-fluorouracil-resistant CRC cell lines and the corresponding secreted exosomes. Six candidate exosomal miRNAs were identified for further evaluating potential value in predicting chemotherapeutic effect in advanced CRC patients. Finally, the molecular mechanisms of these miRNAs in drug resistance were explored by bioinformatics preliminarily.ResultsWe observed that the expression of 14 miRNAs was significantly higher in three drug-resistant CRC cells comparing with their parental cells. Among these miRNAs, miR-21-5p, miR-1246, miR-1229-5p, miR-135b, miR-425 and miR-96-5p are also up-regulated in exosomes from culture media of resistant cells. Clinical sample analysis confirmed that the expression levels of miR-21-5p, miR-1246, miR-1229-5p and miR-96-5p in serum exosomes were significantly higher in chemoresistant patients in contrast with chemosensitive controls. ROC curve showed that the combination of the four miRNAs had an area of under the curve (AUC) of 0.804 (P< 0.05). In addition, GO analysis and KEGG pathway analysis revealed that these miRNAs were enriched in PI3K-Akt signaling pathway, FoxO signaling pathway and autophagy pathway.ConclusionsOur study demonstrates that a panel of serum exosomal miRNAs containing miR-21-5p, miR-1246, miR-1229-5p and miR-96-5p could significantly distinguish the chemotherapy-resistant group from advanced colorectal cancer patients. Targeting these miRNAs may promote chemosensitivity to oxaliplatin and 5-fluorouracil, and might be promising strategy for CRC treatment.