Our study concluded that miR-140-5p hindered cell proliferation, invasion, and tumorigenesis by targeting SOX4 via inactivation of the Wnt/β-catenin and NF-κB signaling pathways in malignant melanoma, which provides an underlying molecular mechanism for the treatment for melanoma with miRNAs.
Collectively, our findings support the notion that targeting the oncogenic β-catenin by lycorine is a new option to inhibit melanoma cell metastasis, providing a good drug candidate potential for development novel therapeutics against metastatic melanoma.
Here, we demonstrated that β-catenin stabilization is a molecular signal subsequent to the onset of Tspan8 expression, and that, in turn, β-catenin triggers the direct transcriptional activation of Tspan8 expression, leading to melanoma invasion.
To investigate the underlying mechanisms, levels of c-Myc, β-catenin, phosphorylated retinoblastoma (p-Rb), cyclin-dependent kinase 4 (CDK4), and Cyclin D3 proteins were determined by western blotting in melanoma A375 cells with WSB2 knocked down.
We performed immunohistochemistry with immune-cell enumeration, immunotyping, and vascular density scoring in genetically engineered (Braf/Pten and Braf/Pten/β-catenin) and transplantable (B16-F1, B16-OVA, and B16-AAD) murine melanomas.
Nuclear β-catenin expression was positive in 98/100 DPN and 2/16 of melanomas (one SSM and one nevoid melanoma with a plexiform clone) and was negative in all 30 Spitz, 26 blue, and 6 PEM lesions.
SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas.
The review took into account the aspects related the Wnt/β-catenin pathway-related epithelial-mesenchymal transition (EMT) versus mesenchymal-epithelial transition (MET) of keratinocytes, fibroblasts and melanoma cells, as possible tools for understanding genesis and evolution of malignant melanoma.
β-catenin is a main driver in melanocyte development; although infrequently mutated in melanoma, its cellular localization and activity are frequently altered.
Loss of beta-catenin expression has been associated with more aggressive clinical disease in cutaneous melanoma, but its status in conjunctival melanocytic lesions is not known, therefore we incorporated beta-catenin immunohistochemical staining in our study.
Interestingly, melanoma cells expressing relative low level of β-catenin and an invasive markers signature were associated to the TNF-α-induced pro-inflammatory pathway and to the chemotherapy resistance, suggesting that the co-existence of melanoma subpopulations with distinct biological properties could influence the impact of chemo- and immunotherapy.
Unexpectedly, β-catenin acts mainly independent of the TCF/LEF dependent canonical Wnt-signaling pathway in resistance development, which partly explains previous contradictory results about the role of β-catenin in melanoma progression and therapy resistance.
Although the role of WNT/β-catenin pathway in melanoma was early demonstrated, its contribution to the lack of the melanoma patient response to treatment was only recently recognized.
We, therefore, designed a novel genetic approach to deactivate stromal fibroblasts at the onset of melanoma formation by targeted ablation of β-catenin.
Several transcription factors and signaling pathways involved in the regulation of MITF expression and/or activity such as the Wnt/β-catenin pathway are broadly utilized by various types of tumors, whereas others, e.g., BRAF(V600E)/ERK1/2 are more specific for melanoma.
Cell lines harboring mutant B-RAF or N-RAS were equally sensitive to LY2090314 as were those with acquired resistance to the BRAF inhibitor Vemurafenib. shRNA studies demonstrated that β-catenin stabilization is required for apoptosis following treatment with the GSK3 inhibitor since the sensitivity of melanoma cell lines to LY290314 could be overcome by β-catenin knockdown.
A multifactorial analysis using Cox's regression model revealed that β-catenin, lymphoid enhancer-binding protein-1, heparanase-1, and the TNM stage were all independent factors in malignant melanoma (risk ratios were 7.294, 5.550, 5.622, and 4.794; p-values were 0.007, 0.018, 0.018, and 0.029, respectively).