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.
Highlights
Uveal melanoma (UM) is a rare tumor of the eye that gives rise to metastases, especially in the liver, and is deadly in about one half of cases
Since our previous studies showed that ADAM10 processes surface c-Met and mediates c-Met ecto-domain shedding [19], we studied the possible effects of miR122 and miR144 mimic transfection on the release of soluble c-Met in the culture supernatant
We have previously shown that both ADAM10 and c-Met are significantly more expressed in primary UM of patients undergoing liver metastases during follow-up, compared to those with good prognosis [14]
Summary
Uveal melanoma (UM) is a rare tumor of the eye that gives rise to metastases, especially in the liver, and is deadly in about one half of cases. Metastases are insensitive to chemotherapy, thereby leading to a high mortality rate [1,2,3]. Inactivating mutations in the BAP1 gene, which is located on chromosome 3, confer a more aggressive behavior to UM [9,10,11]. Mutations in TP53, BRAF, NRAS, TERT and the CDKN2 genes, which are common in cutaneous melanoma [12,13], are rare in UM [1]. High expression of a disintegrin metalloproteinase 10 (ADAM10)
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