Integrative Omics Analysis to Reveal the Molecular Biological Mechanism of Breast Cancer Brain Metastasis

摘要

MDA-MB-231 showed less differences than other cell lines compared with 231BR. This is expected since 231BR is a subline of MDA-MB-231. Overall 1.25 billion paired end reads were generated in deep RNA sequencing which permitted 14551 differentially expressed genes in all six cell lines compared with 231BR. According to the Gene Ontology (GO) analysis, cellular process and binding function are the most important biological process and molecular function, associated with differentially expressed genes. 29 genes were found associated with MAPK, cell-cell adhesion and VEGF signaling pathways which contribute to the cell migration. According to the proteomics analysis, 7071 unique peptides corresponding to 1158 proteins were identified and 772 proteins were quantified in all 3 replicates. 374 proteins showed significantly differential expressions compared with 231BR. Among them, 30 proteins shown differential expression in at least 4 comparisons were verified by MRM. GO analysis showed that cell motion and binding functions are the most important biological process and molecular function, respectively. According to glycomicsanalysis, more than 50 N-glycan structures were identified and quantitatively compared among the six cell lines. The intensities of sialylatedN-glycan structures were highest in 231BR, followed by 361 and 231. High-mannose and fucosylatedglycan structures were more expressed in 231BR than 361. Comparison of transcriptomicsand proteomics data showed that 77 genes/proteins had similar differential expression pattern. These genes/proteins are involved in focal adhesion, regulation of actin skeleton and extra cellular matrix (ECM)-receptor interaction pathways which are important to cell migration. The up-regulation of ITGA2 gene and down-regulation of HSPB1 gene may directly affect the breast cancer cell brain metastasis process. Comparison of glycosylation genes showed that most of the genes in glycosylation pathways were differentially expressed in 231BR and were correlated to the differential expressions of N-glycans. The overexpression of sialylation genes and sialylatedglycansin 231BR and 361 suggested the role of sialylatedglycansin assisting cancer cells penetration of blood-brain barrier. ST6GALNAC2, GMAT3, GAMT4 and FUT5 genes were down-regulated while ST6GALNAC5, POFUT1 and B4GALT6 genes were up-regulated in 231BR relative to the other cell lines. These genes are believed to be important in breast cancer brain metastasis.