Role of miR‐214 in regulation of β‐catenin and the malignant phenotype of melanoma

Abstract

Wnt/β‐catenin signaling plays an important role in melanocyte biology, especially in the early stages of melanocyte transformation and melanomagenesis. β‐catenin, encoded by the gene CTNNB1, is an intracellular signal transducer of Wnt signaling and activates transcription of genes important for cell proliferation and survival. Wnt/β‐catenin signaling is frequently activated in melanoma through oncogenic mutations of β‐catenin and elevated β‐catenin levels are positively correlated with melanoma aggressiveness. Molecular mechanisms that regulate β‐catenin expression in melanoma are not fully understood. MicroRNA‐214 is known to function as a tumor suppressor by targeting β‐catenin in several types of cancer cells. Here, we investigated the regulation of β‐catenin by miR‐214 and its role in melanoma. We show that β‐catenin mRNA levels are negatively correlated with miR‐214 in melanoma. However, overexpression of miR‐214 paradoxically increased β‐catenin protein levels and promoted malignant properties of melanoma cells including resistance to mitogen‐activated protein kinase inhibitors (MAPKi). RNA‐seq analysis revealed that melanoma cells predominantly express a β‐catenin mRNA isoform lacking miR‐214 target site. Using matched miRNA and mRNA‐seq and bioinformatics analysis, we identified novel miR‐214 targets, ankyrin repeat domain 6 (ANKRD6) and C‐terminal binding protein 1 (CTBP1), that are involved in negative regulation of Wnt signaling. Overexpression of miR‐214 or knockdown of the novel miR‐214 targets, ANKRD6 or CTBP1, increased melanoma cell proliferation, migration, and decreased sensitivity to MAPKi. Our data suggest that in melanoma cells β‐catenin is not regulated by miR‐214 and the functions of miR‐214 in melanoma are mediated partly by regulating proteins involved in attenuation of Wnt/β‐catenin signaling.

A novel lncRNA-mRNA-miRNA signature predicts recurrence and disease-free survival in cervical cancer

“…Overexpression of miR-1275 promoted cancer cell migration, invasion, and proliferation ( 18 ), which may be related to its negative regulation on the downstream target genes (such as leucine zipper putative tumor suppressor 3) and then to enhance the stemness of cancer cells ( 17 ). Knockdown of ANKRD6 was revealed to increase melanoma cell proliferation and migration ( 19 ). Consistent with these studies, we also identified CD27-AS1 and ANKRD6 were downregulated, while miR-1275 was upregulated in recurrent CC tissues compared with non-recurrent controls.…”

Identification of a Potentially Functional circRNA-miRNA-mRNA Regulatory Network in Melanocytes for Investigating Pathogenesis of Vitiligo

“…And these circRNA-miRNA-mRNA regulatory networks may play an important role in the pathological mechanism of vitiligo. For instance, hsa-miR-149-5p targets genes SEMA4D (ENSG00000187764) and ANKRD6 (ENSG00000135299) are involved in regulating melanocyte survival and growth ( Soong et al, 2012 ; Prabhakar et al, 2019 ). Sema4D is a paracrine factor that protects normal human melanocytes to survive under ultraviolet (UV) radiation.…”

Is miRNA Regulation the Key to Controlling Non-Melanoma Skin Cancer Evolution?

“…In patients who undergo targeted therapy with BRAF (v-raf murine sarcoma viral oncogene homolog B1) and MEK (mitogen-activated protein kinase) inhibitors the expression of downregulated miRNA-579-3p is associated with treatment resistance, but miRNA-126-3p is responsible for increasing the sensitivity in dabrafenib-resistant patients [ 96 , 97 ]. Chemosensitivity of the malignant cells was correlated with the expression of miRNA-211 but the sensitivity to MAPK inhibitors is decreased when miRNA-214 is overexpressed [ 98 , 99 ]. Referring to immunotherapy in melanoma, the most innovative treatment option implemented so far, miRNAs can be further used as blood markers for efficacy by measuring their plasmatic levels before starting the treatment [ 100 ].…”