MiRNAs Correlate with HLA Expression in Uveal Melanoma: Both Up- and Downregulation Are Related to Monosomy 3

Abstract

MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I expression and inflammation. We also determined whether such miRNAs were related to the UM’s genetic status. The expression of 125 miRNAs was determined in 64 primary UM from Leiden. Similarly, the mRNA expression of HLA-A, HLA-B, TAP1, BAP1, and immune cell markers was obtained. Expression levels of 24 of the 125 miRNAs correlated with expression of at least three out of four HLA Class I probes. Four miRNAs showed a positive correlation with HLA expression and infiltration with leukocytes, 20 a negative pattern. In the first group, high miRNA levels correlated with chromosome 3 loss/reduced BAP1 mRNA expression, in the second group low miRNA levels. The positive associations between miRNA-22 and miRNA-155 with HLA Class I were confirmed in the TCGA study and Rotterdam cohort, and with TAP1 in the Rotterdam data set; the negative associations between miRNA-125b2 and miRNA-211 and HLA-A, TAP1, and CD4 were confirmed in the Rotterdam set. We demonstrate two patterns: miRNAs can either be related to a high or a low HLA Class I/TAP1 expression and the presence of infiltrating lymphocytes and macrophages. However, both patterns were associated with chromosome 3/BAP1 status, which suggests a role for BAP1 loss in the regulation of HLA expression and inflammation in UM through miRNAs.

Genetic and Epigenetic Features of Uveal Melanoma—An Overview and Clinical Implications

“…A study conducted by Souri et al compared the expressions of HLA and miRNA in the same tumors using mRNA expression with four unlined HLA Class I probes [ 88 ]. The study showed that one cluster of miRNAs was positively matched with HLA Class I and infiltrating leukocytes, while the other showed the opposite effect.…”

“…The study also confirmed the relationship between both miRNA expression patterns and chromosome 3 (BAP1) status in UM. This finding could be the starting point to consider miRNAs as regulators of inflammation in UM, regulated by BAP1 [ 88 ].…”

Genetic Basis and Molecular Mechanisms of Uveal Melanoma Metastasis: A Focus on Prognosis

“…Both miRNAs expression patterns in UM show a relation are to chromosome 3/BAP1 status. This study could be the starting point to consider the miRNAs as regulators of inflammation in UM, regulated by BAP1 ( 138 ).…”

Is Tissue Still the Issue? The Promise of Liquid Biopsy in Uveal Melanoma

“… miR-146a [ 97 ] Upregulated in metastatic patients Plasma RT-PCR miR-155 [ 97 ] Upregulated in metastatic patients Plasma RT-PCR Is upregulated in UM-tumors and promotes invasion and proliferation by targeting Nedd4-family interactive protein 1 (NDFIP1). NDFIP1 is necessary for ubiquitination and translocation of, tumor suppressor, PTEN [ 116 , 117 , 118 ]. Upregulation is correlated to monosomy 3 status [ 118 ].…”

“…NDFIP1 is necessary for ubiquitination and translocation of, tumor suppressor, PTEN [ 116 , 117 , 118 ]. Upregulation is correlated to monosomy 3 status [ 118 ]. miR-155 [ 94 ] Downregulated in UM-patients VH and VH EVs TLDA miR-181a [ 97 ] Downregulated in metastatic patients Plasma RT-PCR Upregulation inhibits CTD small phosphatase like (CTDSPL) expression, which in turn promotes cell cycle progression in UM cells [ 119 ].…”