A Systematic Approach to Defining the microRNA Landscape in Metastasis

Abstract

The microRNA (miRNA) landscape changes during the progression of cancer. We defined a metastasis-associated miRNA landscape using a systematic approach. We profiled and validated miRNA and mRNA expression in a unique series of human colorectal metastasis tissues together with their matched primary tumors and corresponding normal tissues. We identified an exclusive miRNA signature that is differentially expressed in metastases. Three of these miRNAs were identified as key drivers of an EMT-regulating network acting though a number of novel targets. These targets include SIAH1, SETD2, ZEB2, and especially FOXN3, which we demonstrated for the first time as a direct transcriptional suppressor of N-cadherin. The modulation of Ncadherin expression had significant impact on migration, invasion, and metastasis in two different in vivo models. The significant deregulation of the miRNAs defining the network was confirmed in an independent patient set as well as in a database of diverse malignancies derived from more than 6,000 patients. Our data define a novel metastasis-orchestrating network based on systematic hypothesis generation from metastasis tissues. Cancer Res; 75(15); 3010-9. Ó2015 AACR.

Function and significance of MicroRNAs in benign and malignant human stem cells

“…Interestingly, some of these miRNAs also play important roles in maintaining self-renewal in hESCs/iPSCs and include members of the miR-200 family, miRs34a/b/c and let-7, see chapters 1 and 2. Recently, we looked at the miRNA landscape in colorectal cancer and identified a signature of significantly deregulated miRNAs that foster metastasis that also included miRs-34,-143, -122 and -200 (114). All of these miRNAs have been implicated in directing stem-cell fate, supporting our hypothesis of similarities between the embryonic cell state and metastasis.…”

Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210

“…We therefore investigated if exosomes might represent a mechanism trough which adherent HCT-8 cells communicate with neighboring disseminated cancer cells and modify their adhesion. The ability of HCT-8 cells to actually secrete exosomes was confirmed by transmission electron microscopy: cytoplasmic structures identical to those described in exosomes secreting cells were infact identified 22 . Electron microscopy also demonstrated the presence of extracellular microvesicles nearby metastatic cells incubated with exosomes secrete by adherent HCT-8 cells.…”

“…In recent years, exosomes have received increasing attention for their role in regulating and transferring molecules responsible for tumor progression and metastasis 22 . We therefore investigated if exosomes might represent a mechanism trough which adherent HCT-8 cells communicate with neighboring disseminated cancer cells and modify their adhesion.…”

“…miR-210 was significantly up-regulated in exosomes compared to its intracellular levels in adherently growing HCT-8 cells and correlated to anoikis resistance and EMT markers. Mudduluru and coworkers, recently performed a systematic analysis of the metastasis-associated miRNome 22 . These authors demonstrated that colorectal cancer cell lines transfected with miR-210 displayed a significant decrease in E-cadherin expression and a parallel increase of N-cadherin expression, an increased migration and invasive capacity and an enhanced ability to metastasize in vivo .…”

The transcription factor FOXN3 inhibits cell proliferation by downregulating E2F5 expression in hepatocellular carcinoma cells

“…Moreover, FOXN3 inhibits cell proliferation by repressing PIM2 and protein biosynthesis [19]. FOXN3 also suppresses the expression of N-cadherin mRNA and protein by transcriptionally repressing N-cadherin promoter activity [20]. However, the role of FOXN3 in HCC tumorigenesis remains poorly understood.…”