Distinguishing Tumor and Stromal Sources of MicroRNAs Linked to Metastasis in Cutaneous Melanoma

Abstract

MicroRNA (miRNA) dysregulation in cancer causes changes in gene expression programs regulating tumor progression and metastasis. Candidate metastasis suppressor miRNA are often identified by differential expression in primary tumors compared to metastases. Here, we performed comprehensive analysis of miRNA expression in The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) tumors (97 primary, 350 metastatic), and identified candidate metastasis-suppressor miRNAs. Differential expression analysis revealed miRNA significantly downregulated in metastatic tumors, including miR-205, miR-203, miR-200a-c, and miR-141. Furthermore, sequential feature selection and classification analysis identified miR-205 and miR-203 as the miRNA best able to discriminate between primary and metastatic tumors. However, cell-type enrichment analysis revealed that gene expression signatures for epithelial cells, including keratinocytes and sebocytes, were present in primary tumors and significantly correlated with expression of the candidate metastasis-suppressor miRNA. Examination of miRNA expression in cell lines revealed that candidate metastasis-suppressor miRNA identified in the SKCM tumors, were largely absent in melanoma cells or melanocytes, and highly restricted to keratinocytes and other epithelial cell types. Indeed, the differences in stromal cell composition between primary and metastatic tumor tissues is the main basis for identification of differential miRNA that were previously classified as metastasis-suppressor miRNAs. We conclude that future studies must consider tumor-intrinsic and stromal sources of miRNA in their workflow to identify bone fide metastasis-suppressor miRNA in cutaneous melanoma and other cancers.

The inhibitory role of microRNA-141-3p in human cutaneous melanoma growth and metastasis through the fibroblast growth factor 13-mediated mitogen-activated protein kinase axis

“…Initial experimentation in our study revealed that miR-141-3p was poorly expressed, and FGF13 was highly expressed in CM tissues. In line with our data, Watt et al [37] also previously documented downregulation of miR-141 in melanoma. Subsequent microarray-based screening analyses in our study highlighted that there was a correlation among the FGF13, CDH1, SYK, and FN1 genes in the context of melanoma.…”

Integration of p16/HPV DNA Status with a 24-miRNA-Defined Molecular Phenotype Improves Clinically Relevant Stratification of Head and Neck Cancer Patients

“…Although the overlap of miRNAs from different HNSCC studies is generally relatively small, 12 of the differentially expressed miRNAs between HPV-positive and HPV-negative tumours ( Table S1 ) and five signature miRNAs (hsa-miR-155-5p, hsa-miR-181a-5p, hsa-miR-18a-5p, hsa-miR-378a-3p, hsa-miR-455-3p) were previously reported to be HPV-associated [ 1 , 5 , 6 , 7 , 8 , 9 , 10 , 12 ]. The analysis of bulk samples does not allow differentiation between tumour and stromal miRNA sources (e.g., infiltrated lymphocytes), and could be a cause for the rather small differences in detected miRNA levels [ 36 ]. Nevertheless, the miRNA analyses enabled the identification of a 24-miRNA signature that, in addition to miRNA expression differences in tumour cells, could also be determined by those of the tumour microenvironment of HPV-positive and HPV-negative patients.…”

Critical Considerations for Investigating MicroRNAs during Tumorigenesis: A Case Study in Conceptual and Contextual Nuances of miR-211-5p in Melanoma

“…Ultimately, we restricted our further analyses to studies that clearly identified the disease subtypes in each cohort and attributed at least one dermatopathologist was attributed as reviewing each specimen. We identified twenty-one studies that met these criteria [ 47 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ].…”

“…However, in addition to directionality, the magnitude of differential expression should also be considered when assessing the biological function of a miRNA ( Figure 2 , Figure 3 and Figure 4 ). MiR-211 is usually detectable in primary melanoma specimens, and its expression is approximately 2–10-fold greater in melanocytic nevi [ 47 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ]. In comparison, expression of the miRNA is routinely reported at 10 2 –10 4 -fold greater in cultured NHEMs, as compared to cultured human melanoma lines [ 112 , 118 , 127 , 129 ].…”