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Abstract
Recent high-throughput-sequencing of cancer genomes has identified oncogenic mutations in the B-Raf genetic locus as one of the critical events in melanomagenesis. B-Raf encodes a serine/threonine kinase that regulates the MAPK/ERK kinase (MEK) and extracellular signal-regulated kinase (ERK) protein kinase cascade. In normal cells, the activity of B-Raf is tightly regulated and is required for cell growth and survival. B-Raf gain-of-function mutations in melanoma frequently lead to unrestrained growth, enhanced cell invasion and increased viability of cancer cells. Although it is clear that the invasive phenotypes of B-Raf mutated melanoma cells are stringently dependent on B-Raf-MEK-ERK activation, the downstream effector targets that are required for oncogenic B-Raf-mediated melanomagenesis are not well defined. miRNAs have regulatory functions towards the expression of genes that are important in carcinogenesis. We observed that miR-10b expression correlates with the presence of the oncogenic B-Raf (B-RafV600E) mutation in melanoma cells. While expression of miR-10b enhances anchorage-independent growth of B-Raf wild-type melanoma cells, miR-10b silencing decreases B-RafV600E cancer cell invasion in vitro. Importantly, the expression of miR-10b is required for B-RafV600E-mediated anchorage independent growth and invasion of melanoma cells in vitro. Taken together our results suggest that miR-10b is an important mediator of oncogenic B-RafV600E activity in melanoma.
Highlights
Melanoma is the most aggressive of all the skin cancers
We previously reported that the expression of several miRNAs was altered upon introduction of B-RafV600E in primary melanocytes [16]
Among the miRNAs whose expression levels were affected by B-RafV600E, we chose miR-10b for further study because its expression positively correlates with V600E mutation in B-Raf in established melanoma cell lines (Fig 1), clinical melanoma samples (S1 Fig), and because it is involved in several other malignancies [17]
Summary
Melanoma is the most aggressive of all the skin cancers. B-Raf is a serine/threonine protein kinase that activates the MEK/ERK-signaling pathway. Critical role of miR-10b in B-RafV600E dependent anchorage independent growth and invasion of melanoma cells Among the miRNAs whose expression levels were affected by B-RafV600E, we chose miR-10b for further study because its expression positively correlates with V600E mutation in B-Raf in established melanoma cell lines (Fig 1), clinical melanoma samples (S1 Fig), and because it is involved in several other malignancies [17].
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