蚁群优化算法构建乳腺癌中miRNA调控的关键基因互作网络

Construction of key gene interaction network of miRNA regulation in breast cancer by ant colony optimization

目的筛选ER阳性乳腺癌中受miRNA调控的关键基因,以此构建乳腺癌中miRNA-mRNA互作网络,进而了解ER阳性乳腺癌的调控机制,为筛选ER阳性乳腺癌诊断预后的生物标志物和治疗靶点打下基础。方法利用MCF-7细胞系的AGO-IP(HITS-CLIP Protocol for Argonaute)高通测序实验数据,发现miRNA对mRNA的真实调控关系,并以此构建基于RNAs诱导的沉默复合体(RNA-induced silencing complex,RISCs)miRNA-mRNA调控模组。根据调控模组利用蚁群优化算法在基因互作网络中筛选关键基因,构建ER阳性乳腺癌中miRNA调控下的关键基因互作网络,并对关键基因进行功能分析。结果本研究筛选出106个关键基因,244个调控关键基因的miRNA。根据乳腺癌中miRNA调控的关键基因互作网络识别出了 YWHAG、EP300、CHEK1、SMAD2、SMAD1、SYK、FGFR1、PIK3R2、IRS1、TGFBR2、CHUK和CSDE1等12个hub基因;并发现了hsa-miR-940、hsa-miR-545-3p、hsa-miR-3065-5p、hsa-miR-15a-5p、hsa-miR-181b-5p、hsa-miR-16-5p、hsa-miR-765、hsa-miR- 4723-5p 、hsa-miR-454-3p、hsa-miR-374a-5p、hsa-miR-34a-5p、hsa-miR-30e-5p、hsa-miR-19a-3p、hsa-miR-15b-5p、hsa-miR-149-5p和hsa-miR-128-3p等16个hub miRNA。这些基因主要对肿瘤细胞的增殖、侵袭、化疗抗性、放疗抗性和耐药性起重要作用。结论本研究筛选出的关键基因及调控关键基因的miRNA对ER阳性乳腺癌的耐药性、化疗抗性、放疗抗性及肿瘤细胞的增殖、侵袭有重要调控作用,对ER阳性乳腺癌临床治疗及预后起到重要参考作用。

Objective To screen the key genes regulated by miRNA in ER+ breast cancer,and construct the miRNA-mRNA interaction network in breast cancer,so as to understand the regulatory mechanism of ER+ breast cancer,and lay the foundation for screening the biomarkers and treatment targets of ER+ breast cancer for diagnosis and prognosis. Methods By using the high-pass sequencing data of AGO-IP (HITS-CLIP Protocol for Argonaute) of MCF-7 cell line,we found the real relationship between miRNA and mRNA,and constructed a miRNA-mRNA regulatory module based on RNAs-induced silencing complex (RISC). According to the regulation module,ant colony optimization algorithm was used to screen key genes in gene interaction network,and constructed the key gene interaction network under the regulation of miRNA in ER+ breast cancer,and analyzed the function of key genes. Results In this study,106 key genes and 244 microRNAs regulating key genes were screened. Twelve hub genes,including YWHAG,EP300,CHEK1,SMAD2,SMAD1,SYK,FGFR1,PIK3R2,IRS1,TGFBR2,CHUK,CSDEE1,and 16 hub miRNAs,including hsa-miR-940,hsa-miR-545-3p,hsa-miR-3065-5p,hsa-miR- 15a-5p ,hsa-miR- 181b-5p ,hsa-miR-16-5p,hsa-miR-765,hsa-miR-4723-5p,hsa-miR-454-3p,hsa-miR-374a-5p,hsa-miR-34a-5p,hsa-miR-30e-5p,hsa-miR-19a-3p,hsa-miR-15b-5p,sa-miR-149-5p,hsa-miR-128-3p ,were identified according to the key gene interaction network regulated by miRNA in breast cancer. These genes played an important role in the proliferation,invasion,chemotherapy resistance,radiotherapy resistance and drug resistance of cancer cells. Conclusions In this study,we screened out the key genes and the miRNA that regulated the key genes,which played an important role in the regulation of ER+ breast cancer resistance,chemotherapy resistance,radiotherapy resistance,proliferation and invasion of cancer cells. It also played an important reference role in the clinical treatment and prognosis of ER+ breast cancer.