New Target Genes of MITF-Induced microRNA-211 Contribute to Melanoma Cell Invasion

Abstract

The non-coding microRNAs (miRNA) have tissue- and disease-specific expression patterns. They down-regulate target mRNAs, which likely impacts on most fundamental cellular processes. Differential expression patterns of miRNAs are currently being exploited for identification of biomarkers for early disease diagnosis, prediction of progression for melanoma and other cancers and as promising drug targets, since they can easily be inhibited or replaced in a given cellular context. Before successfully manipulating miRNAs in clinical settings, their precise expression levels, endogenous functions and thus their target genes have to be determined. MiR-211, a melanocyte lineage-specific small non-coding miRNA, is located in an intron of TRPM1, a target gene of the microphtalmia-associated transcription factor (MITF). By transcriptionally up-regulating TRPM1, MITF, which is critical for both melanocyte differentiation and survival and for melanoma progression, indirectly drives the expression of miR-211. Expression of this miRNA is often reduced in melanoma samples. Here, we investigated functional roles of miR-211 by identifying and studying new target genes. We show that MITF-correlated miR-211 expression levels are mostly but not always reduced in a panel of 11 melanoma cell lines and in primary and metastatic melanoma compared to normal melanocytes and nevi, respectively. MiR-211 itself only marginally impacted on cell invasion and migration, while perturbation of some new miR-211 target genes, such as AP1S2, SOX11, IGFBP5, and SERINC3 significantly increased invasion. These results and the variable expression levels of miR-211 raise serious doubts on the value of miR-211 as a melanoma tumor-suppressing miRNA and/or as a biomarker for melanoma.

BRAFV600inhibition alters the microRNA cargo in the vesicular secretome of malignant melanoma cells

“…It was further suggested that miR-211 acts as a molecular switch that is usually turned off in many melanomas, and figuring out how and when to turn this switch on might provide insights into better treatment for melanomas (29,30). Our finding that miR-211-5p is increased in cells upon vemurafenib treatment could support the development of more targeted therapies against melanoma cells in which miR-211 is up-regulated.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Microphthalmiaassociated transcription factor (MITF), a melanocytic marker used in diagnostic surgical pathology, is a major regulator of TRPM1 expression (Miller et al, 2004). MITF is also required for miR-211 expression, suggesting that the tumor suppressor activities of MITF and/or TRPM1 may at least partially be due to miR-211 (Mazar et al, 2010;Margue et al, 2013).…”

“…The Trpm1 gene codes two transcripts: TRPM1 channel protein in its exons and miR-211 in one of its introns. The loss of TRPM1 channel protein is an excellent marker of melanoma aggressiveness, whereas the expression of miR-211 is linked to the tumor suppressor function of TRPM1 (Mazar et al, 2010;Guo et al, 2012;Margue et al, 2013).…”

MicroRNA-211 Enhances the Oncogenicity of Carcinogen-Induced Oral Carcinoma by Repressing TCF12 and Increasing Antioxidant Activity

“…Discussion miR-211 is associated with the pathogenesis of several malignancies including OSCC (14)(15)(16)(17)(19)(20)(21). Studies have elucidated that miR-211 is versatile in targeting multiple genes in different kinds of cells (10, 15-21, 31, 47).…”

“…A recent study has also specified that miR-211 prevents the ER induction by transcriptional repression of C/EBP homologous protein (CHOP) to modulate the survival of cells (18). Despite that miR-211 is a tumor suppressor in melanoma and some other cancers (19)(20)(21), the function of miR-211 as an oncogenic molecule has become more evident in a fraction of malignancies (15)(16)(17)(18).…”