Melanoma, a cancer of the pigment-producing cells in the skin epidermis, can be highly metastatic, and malignant melanomas are relatively resistant to standard chemotherapy 
. A major cause for melanoma initiation is extensive or intermittent exposure to the sun's radiation over a period of time, and the extent of melanin pigmentation is an important risk factor 
. The exact molecular mechanisms that lead to melanoma are complex and poorly understood 
, and may involve both mutagenic DNA lesions and epigenetic misregulation 
. The complexity is added by the involvement of several different signal transduction pathways, such as the Hedgehog
pathway, which controls BCL2-mediated apoptosis; mutations in the Patched
gene, the endpoint of the Hedgehog
pathway, have been correlated with skin cancers 
. A frequent causative mechanism for an inherited form of predisposition to melanoma is thought to be a chromosomal deletion over 9p21. The 9p21 site harbors the tumor suppressor gene INK4a and accompanies additional inactivating mutations that lead to the constitutive activation of genes such as BRAF 
. INK4a encodes one of several cyclin-dependent protein kinase inhibitors, which is located adjacent to an alternate reading frame of the human p14ARF
binds to the Mdm2 protein in several cell lines (though remains untested in melanoma cell lines, to our knowledge) and thereby abrogates Mdm2's binding to p53, causing p53 to be stabilized and nuclear localized. The loss of INK4a therefore may lead to interference of two separate pathways of cell cycle control: CDK signaling and suppression of p53 activity by Mdm2-induced acceleration of p53 degradation. Methylation near the 5′ upstream region of INK4a has been shown in some 10% of melanomas 
, suggesting that epigenetic down-regulation of this gene may be important for melanoma development. The activation of BRAF
alone may be insufficient to cause metastatic melanoma, but additional mutagenic or epigenetic events such as the inactivation of tumor suppressor genes, e.g.
, Pten 
, may be important. There is evidence that the NOTCH
signalling pathway is important for distinguishing normal melanocytes from melanoma cells 
. Measurement of genome-wide DNA copy number variations, together with analysis of somatic mutations in specific marker genes, can be used to distinguish among different melanoma subtypes with reasonable accuracy 
. Particularly noteworthy is the recent demonstration of abnormally high oncogenic potentials of single melanoma cells 
, emphasizing the need for better understanding the molecular mechanisms of melanoma progression.
Attention has recently focused on the role of small non-coding RNA molecules in cancer development 
and in melanoma in particular 
. miRNAs influence cancer development by serving either as tumor suppressors or oncogenes 
by their negative regulatory effects on mRNA encoded by oncogenes or tumor suppressor genes, respectively. With the goal of defining the genes with major contributions to melanoma, several genome-wide expression level studies have identified a number of protein-coding 
and microRNA (miRNA) genes as important players 
. Several of these genes and their expression signatures exhibit distinct patterns among malignant metastatic melanomas and their benign forms, but their significance with respect to melanoma initiation and progression is poorly understood. For example, miR-221/222 were found to down-regulate p27Kip1/CDKN1B and the c-KIT receptor, which controls the progression of neoplasia leading to enhanced proliferation and reduced differentiation in melanoma cells 
. Similarly, high miR-137 expression in melanoma cell lines down-regulates microphthalma associated transcription factor (MITF), a transcription factor important for melanocyte cell growth, maturation, apoptosis, and pigmentation 
. The depletion of miR-182 reduces invasiveness and induces melanoma cell death by suppressing the expression of transcription factors FOXO3 and MITF 
, suggesting that its increased expression may be associated with certain aspects of melanoma biology. Relatively less is known about the downstream genes that are regulated by MITF and FOXO3, which are evidently important for melanoma progression and metastasis.
In contrast to miRNAs that are over-expressed in melanoma, and their respective target genes that are thus under-expressed, relatively little is known about miRNA species that are systematically depleted in melanomas. Consequently, their respective target genes, expected to be up-regulated, which might explain some of the oncogenic potentials of invasive melanomas, are largely unrecognized. Realizing this gap in knowledge, we examined the expression levels of human miRNAs in defined melanoma cell lines and clinical melanoma samples. We report here the reduced expression of miR-211 in these cell lines and clinical isolates of human melanomas, and present evidence that a principal effect of the reduced expression of miR-211 is the increased expression of its target transcript KCNMA1. The expression of KCNMA1, encoding a calcium ion-regulated potassium channel protein, appears to at least partially account for the high cell proliferation rate and invasiveness of melanoma cell lines. We also demonstrate that MITF expression is important for the coordinate expression of miR-211, and TRPM1. TRPM1 gene is a suppressor of melanoma metastasis, which encodes a transient receptor potential family member calcium channel protein, and encodes miR-211 gene in its sixth intron. Here, we propose a model for the role of miR-211 and its regulation in melanoma cells.