MicroRNA-125b suppresses the epithelial–mesenchymal transition and cell invasion by targeting ITGA9 in melanoma

Abstract

Increasing evidence has shown that aberrant miRNAs contribute to the development and progression of human melanoma. Previous studies have shown that miR-125b functions as a suppressor in malignant melanoma. However, the molecular function and mechanism by which miR-125b influences melanoma growth and invasion are still unclear. In this study, we aimed to investigate the role of miR-125b in melanoma progression and metastasis. We found that miR-125b expression is significantly downregulated in primary melanoma, and an even greater downregulation was observed in metastatic invasion. Restored expression of miR-125b in melanoma suppressed cell proliferation and invasion both in vitro and in vivo. Furthermore, our findings demonstrate that upregulating miR-125b significantly inhibits malignant phenotypes by repressing the expression of integrin alpha9 (ITGA9). Finally, our data reveal that upregulated expression of ITGA9 in melanoma tissues is inversely associated with miR-125b levels. Together, our results demonstrate that upregulation of ITGA9 in response to the decrease in miR-125b in metastatic melanoma is responsible for melanoma tumor cell migration and invasion.

Genetics and epigenetics of melanoma

“…One example of this is miR-125b, a negative regulator of the MAPK downstream targeting c-Jun by altering translation or protein stability. The forced expression of miR-125b was found to suppress cell proliferation and migration, in agreement with downregulation of the MAPK pathway (22,23). …”

Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases

“…Potentially beneficial gene changes affected by IFNγ treatment include: downregulation of LPL which encodes for an enzyme that breaks down triglycerides providing an energy source that can promote cancer growth; upregulation of MIR125B1, which is often downregulated in melanoma but if expression is restored can suppress melanoma proliferation and invasion; and upregulation of SECTM1, a T-cell co-stimulatory ligand that promotes CD4 and CD8 T-cell proliferation and induces IFNγ production [39–42]. Conversely, IDO1 and complement C4A,B genes, upregulated post IFNγ treatment, have been shown to impact negatively tumor clearance, potentially being problematic for patients (Table 1) [43,44].…”

The Phosphorylation and Distribution of Cortactin Downstream of Integrin α9β1 Affects Cancer Cell Behaviour

“…The human G361 melanoma cell line is invasive, and as we showed previously has a high level of α9β1 integrin on the cell surface10. Recently, mRNA levels of integrin α9 were shown to be higher in primary human melanoma samples, compared to normal skin samples42. Integrin α9 mRNA is negatively regulated by miRNA-125b, which is downregulated in primary melanoma42.…”

“…Recently, mRNA levels of integrin α9 were shown to be higher in primary human melanoma samples, compared to normal skin samples42. Integrin α9 mRNA is negatively regulated by miRNA-125b, which is downregulated in primary melanoma42. The human rhabdomyosarcoma cell line, RD, also expresses a very high level of cell surface α9 integrin37.…”