MicroRNA-149*, a p53-responsive microRNA, functions as an oncogenic regulator in human melanoma

Abstract

The tumor suppressor p53 is activated in response to cellular stress to prevent malignant transformation by activation of the DNA repair machinery to preserve the cell, or by induction of apoptosis to eliminate the cell should the damage prove irrevocable. The gene encoding p53 frequently undergoes inactivating mutations in many human cancers, but WT p53 is often expressed at high levels in melanoma, which, as judged from the malignant nature of the disease, fails to act as an effective tumor suppressor. Here we show that p53 directly up-regulates microRNA-149* (miR-149*) that in turn targets glycogen synthase kinase-3α, resulting in increased expression of Mcl-1 and resistance to apoptosis in melanoma cells. Although deficiency in miR-149* undermined survival of melanoma cells and inhibited melanoma growth in a mouse xenograft model, elevated expression of miR-149* was found in fresh human metastatic melanoma isolates, which was associated with decreased glycogen synthase kinase-3α and increased Mcl-1. These results reveal a p53-dependent, miR-149*–mediated pathway that contributes to survival of melanoma cells, provides a rational explanation for the ineffectiveness of p53 to suppress melanoma, and identifies the expression of miR-149* as a mechanism involved in the increased expression of Mcl-1 in melanoma cells.

MicroRNA-149 targets specificity protein 1 to suppress human tongue squamous cell carcinoma cell proliferation and motility

“…miRNA is thereby a potential diagnostic and prognostic marker of TSCC with therapeutic potential (18)(19)(20). Previous studies revealed that miR-149 was downregulated in colorectal cancer, breast cancer, gastric cancer, glioma, melanoma and non-small cell lung cancer (21)(22)(23)(24)(25)(26). This study investigated the expression, biological functions and molecular mechanisms of miR-149 in TSCC.…”

MiR-1246: A new link of the p53 family with cancer and Down syndrome

“…6 These miRNAs have also been shown to play a role in controlling cell growth, apoptosis, senescence and autophagy in a p53-dependent fashion ( Table 1). [7][8][9][10][11][12][13][14][15][16][17][18][19][20] Recently, we identified miR-1246 as another novel p53 target miRNA. Interestingly, this miRNA regulates the expression of DYRK1A, a Down syndrome-associated kinase, 21 which inactivates a nuclear transcriptional factor called NFAT1C by phosphorylating it and preventing it from nuclear import.…”

Autoregulation of glypican-1 by intronic microRNA-149 fine-tunes the angiogenic response to fibroblast growth factor in human endothelial cells

“…This regulatory control is carried out through repression of gene expression at the post-transcriptional level (Bartel, 2009). Interestingly, miR-149 is found within the first intron of GPC1 (Jin et al, 2011) and its expression is downregulated in different solid tumors (Jin et al, 2011;Li et al, 2011;Øster et al, 2013;Wang et al, 2013). Moreover, overexpression of miR-149 in glioma and colorectal cancer cells results in reduced proliferation and migration, thus suggesting that miR-149 might play a role as a tumor suppressor (Jin et al, 2011;Li et al, 2011).…”