Abstract
MiR-106b is overexpressed in various types of cancers and is associated with the regulation of the carcinogenic processes. Using RT-PCR, we have identified overexpression of miRNA-106b in various melanoma cell lines (A375, Hs294t, SK-Mel28, SK-Mel 119, Mel 1241, Mel 1011 and Mel 928) as compared to its expression in normal human epidermal melanocytes (NHEM). The overexpression of miR-106b in melanoma cells (A375, Hs294t) was associated with greater cell proliferation capacity than NHEM. Treatment of A375 and Hs294t cells with anti-miR-106b resulted in inhibition of cell proliferation as well as G1-phase arrest. We determined the effects of grape seed proanthocyanidins (GSPs) on the expression of miRNA-106b and its underlying molecular targets. Treatment of A375 and Hs294t cells with GSPs resulted in suppression of the levels of miRNA-106b, cytotoxicity, G1-phase arrest and reactivation of p21/WAF1/Cip1. Dietary GSPs significantly inhibited growth of A375 melanoma cell tumor xenografts in nude mice, which was associated with reduction in the levels of miRNA-106b, tumor cell proliferation and increases in the levels of p21/WAF1/Cip1 protein. These studies suggest that miRNA-106b plays a crucial role in melanoma growth and that GSPs act as an inhibitor of miR-106b thereby blocking melanoma growth in vitro and in vivo models.
Highlights
Malignant melanoma is an aggressive and deadly skin cancer that causes the majority of skin cancer-related deaths [1, 2]
Our cell proliferation assay analysis indicates that the cell proliferation potential of melanoma cell lines (A375, Hs294t, SK Mel 28, SK Mel 119, Mel 1241, Mel 1011, and Mel 928) was several fold higher than that of normal human epidermal melanocytes (NHEM) and that this proliferation potential of melanoma cells is associated with the higher expression of miR-106b
The authors demonstrated that p21/WAF1/Cip1 is a direct target of miR-106b and its downregulation plays an effective role in miR-106b-induced cell cycle progression
Summary
Malignant melanoma is an aggressive and deadly skin cancer that causes the majority of skin cancer-related deaths [1, 2]. Alterations in the expression level of miRNA are correlated with cancer development [5], and play an important role in cell proliferation, cell differentiation, and cell death Many of these miRNAs possess oncogenic or tumor suppressor activity in various tumors [5, 6], but little is known about their potential role in melanoma progression. Cellcycle progression relies on the activation of cyclins and cyclin-dependent kinases (CDKs), which act together in G1 phase to initiate S phase and in G2 phase to initiate mitosis These kinases promote expression of cell cycle genes controlled by E2F transcription factors [17]. When activated in the G1 phase, cyclin D/CDK4, 6 and cyclin E/CDK2 kinases phosphorylate pRb, thereby preventing its association with E2F and allowing E2F transcription factors to induce S-phase gene expression [18]
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