結合生物資訊、網絡分析與功能性研究探討癌症之易感基因

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her2/neu). TNBC has worse clinical outcomes than other breast cancer subtypes. However, the key molecules and mechanisms of TNBC migration remain unclear. In this study, we compared two normalized microarray datasets from GEO database between Asian (GSE33926) and non-Asian populations (GSE46581) to determine the molecules and common pathways in TNBC migration. We demonstrated that 16 genes in non-Asian samples and 9 genes in Asian samples are related to TNBC migration. In addition, our analytic results showed that 4 genes, PIK3R3, ITGB1, ITGAL, and ITGA6, were involved in the regulation of actin cytoskeleton. To validate our result, we selected integrin beta1 (ITGB1) which was one of the crucial genes we discovered and showed the highest degree of connectivity in cellular movement network and functioned as a receptor in regulating the actin cytoskeleton pathway to further study. We combined the data from both Taiwanese patients (GSE53752) and TCGA dataset and reported that higher expression level of ITGB1 correlates with lower survival rates of TNBC patients. We also provide evidence that ITGB1-mediated store-operated calcium influx is involved breast cancer cell migration as well as invasion in this experimental model.
In addition, we also studied the crucial molecules and pathways associated with the presence of lymphovascular invasion (LVI) in breast cancer. To our understanding, LVI has become one of the prognostic markers that help physicians to identify the risk for distant metastasis and recurrence. Differentially expressed genes (DEGs) were performed between LVI-present (LVI+) and LVI-absent (LVI-) cases. Our result showed that there were 37 down-regulated genes and 49 up-regulated genes. We found that TNFSF11, IL6ST and EPAS1 were involved in cytokine-receptor interaction, which was also the most enrichment pathway related to LVI. Moreover, the results also suggested that an imbalance between extracellular matrix (ECM) components and tumor micro-environment could induce LVI. In conclusion our study evaluated the cell migration, prognostic marker LVI and underlying mechanisms which may help physicians to assess the risk of breast cancer progression and provides a potentially candidate biomarker for regulating cell migration.
Besides breast cancer study, we performed pathway and network analysis of oxaliplatin resistance in colon cancer cells. Oxaliplatin is often used in combination regimens such as FOLFOX, CapeOX, and FOLFOXIRI because of the cost-effectiveness of adjuvant treatment for patients and also the good tolerability profile. However, some patients show resistance to oxaliplatin which causes poor treatment outcomes. In this study we performed microarray analysis and found that endothelin-1 (EDN1), dishevelled segment polarity protein (DV1), toll-like receptor 5(TLR5), mitogen-activated protein kinase kinase 3 (MAP2K3), phosphatidylinositol-4,5-bisphosphate 3-kinase, and catalytic subunit beta (PIK3CB) were closely related to responsiveness to oxaliplatin treatment. Furthermore, we found that the signal transduction, melanogenesis, and toll-like receptor signaling pathways might be involved in oxaliplatin-resistant colon cancer. These genes and pathways might be potential targets for improving oxaliplatin treatment in colon cancer patients.