Potential Onco-Suppressive Role of miR122 and miR144 in Uveal Melanoma through ADAM10 and C-Met Inhibition

Abstract

Uveal melanoma (UM) is a rare tumor of the eye that leads to deadly metastases in about half of the patients. ADAM10 correlates with c-Met expression in UM and high levels of both molecules are related to the development of metastases. MiR122 and miR144 modulate ADAM10 and c-Met expression in different settings. We hypothesized a potential onco-suppressive role for miR122 and miR144 through modulation of ADAM10 and c-Met in UM. We analyzed the UM Cancer Genome Atlas data portal (TCGA) dataset, two other cohorts of primary tumors and five human UM cell lines for miR122 and miR144 expression by miR microarray, RT-qPCR, Western blotting, miR transfection and luciferase reporter assay. Our results indicate that miR122 and miR144 are expressed at low levels in the UM cell lines and in the TCGA UM dataset and were down-modulated in a cohort of seven UM samples, compared to normal choroid. Both miR122 and miR144 directly targeted ADAM10 and c-Met. Overexpression of miR122 and miR144 led to reduced expression of ADAM10 and c-Met in the UM cell lines and impaired cell proliferation, migration, cell cycle and shedding of c-Met ecto-domain. Our results show that miR122 and miR144 display an onco-suppressive role in UM through ADAM10 and c-Met modulation.

MicroRNAs and Uveal Melanoma: Understanding the Diverse Role of These Small Molecular Regulators

“…Finally, miR-34a response elements (MREs) have been used to help direct a TRAIL-expressing adenoviral vector in UM cell lines and UM xenografts with high anti-tumour activity, thereby helping to improve specificity of drugs [98]. Most recently, Amaro et al, investigated the regulation of metastatic genes ADAM10 and c-Met by miR-122 and miR-144 [99]. In this study, they confirmed downregulation of both miRNAs by microarray analysis in primary UM samples and cell lines, and analysed the TCGA database to validate their findings.…”

“…In this study, they confirmed downregulation of both miRNAs by microarray analysis in primary UM samples and cell lines, and analysed the TCGA database to validate their findings. Further analysis showed that overexpression of miR-122 and miR-144 reduced ADAM10 and c-Met protein expression resulting in reduced proliferation, migration and cell cycle progression [99].…”

“…Most recently, Amaro et al, investigated the regulation of metastatic genes ADAM10 and c-Met by miR-122 and miR-144 [ 99 ]. In this study, they confirmed downregulation of both miRNAs by microarray analysis in primary UM samples and cell lines, and analysed the TCGA database to validate their findings.…”

RNA-Interference-Mediated miR-122-Based Gene Regulation in Colon Cancer, a Structural In Silico Analysis

“…miR-122 has been regarded as a potential tumor suppressor miRNA in various types of cancers including gastric cancer, rectal cancer, hepatocellular carcinoma, gallbladder cancer, uveal melanoma, and breast cancer [ 23 , 24 ]. The function of miR-122 and its associated mRNAs such as TRIM29, Bcl-W, CCNG1, CDC25A, XIAP, and ALDOA are reportedly downregulated during cancer cell progression [ 11 , 12 , 13 , 14 ].…”

The Role of Non-Coding RNAs in Uveal Melanoma

“…Similar to miR-34a, C-Met has been identified as a target of miR-34b/c; other agents involved in the c-Met signaling pathway, such as p-Akt, CDK4, and CDK6, were also detected as underexpressed upon introduction of miR-34b/c in UM [ 25 ]. In a similar way, overexpression of miR-122 and miR-144 can also reduce the expression of c-Met and ADAM10 proteins, resulting in reduced proliferation, migration, and cell cycle progression in UM [ 26 ].…”