Abstract
Melanoma is the most aggressive form of skin cancer with estimated 48,000 deaths per year worldwide. The polyphenol curcumin derived from the plant Curcuma longa is well known for its anti-inflammatory and anti-cancerogenic properties. Accordingly, dietary intake of this compound may be suitable for melanoma prevention. However, how this compound affects basic cellular mechanisms in developing melanoma still remains elusive. Therefore, the aim of this study was to investigate for the first time the impact of oral curcumin administration on the miRNA signature of engrafting melanoma. For this purpose, the effects of a 4% curcumin diet were tested on melanoma, which were established by injection of murine B78H1 cells in the flank of C57BL/6 mice. Curcumin diet or standard chow (control) was administered two weeks prior to injection of tumor cells until termination of the experiment. High throughput chip-based array analysis was deployed to detect alterations in the miRNA signature of the tumors. Curcumin treatment significantly reduced the growth of the flank tumors. Furthermore the miRNA expression signature in tumors was substantially altered by curcumin intake with mmu-miR-205-5p over 100 times higher expressed when compared to controls. The expression levels of identified key miRNAs in the tumor samples were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR). A comparable expression pattern of these miRNAs was also detected in other curcumin-treated melanoma cell lines under in vitro conditions. Putative targets of curcumin-induced up-regulated miRNAs were enriched in ‘o-glycan biosynthesis’, ‘endoplasmatic reticulum protein processing’ and different cancer-related pathways. Western Blot analyses revealed that of these targets anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) and proliferating cell nuclear antigen (PCNA) were significantly down-regulated in curcumin-treated tumors. These findings demonstrate a profound alteration of the miRNA expression signature in engrafting curcumin-treated melanoma with mmu-miR-205-5p being up-regulated most significantly.
Highlights
Small non-coding RNAs, so-called microRNAs, post-transcriptionally attenuate many cellular processes [1,2]
In the present study we investigated the effects of oral curcumin intake on melanoma growth with the goal to identify potential changes of the tumor miRNA signature
The expression levels of mmu-miR-205-5p, mmumiR-205-3p, mmu-miR-142-5p and mmu-miR-130b-3p, which have previously been described in the literature as miRNAs with potential anti-cancer properties [37,38], were confirmed by qRTPCR (Figure 2). We found these key miRNAs regulated by curcumin in cultured murine B78H1 cells and human SK-MEL-28 cells (Figure 3)
Summary
Small non-coding RNAs, so-called microRNAs (miRNAs, miRs), post-transcriptionally attenuate many cellular processes [1,2]. These evolutionary conserved miRNAs are about 22 nucleotides long and decrease protein expression in proliferating cells by binding to corresponding mRNAs leading either to transcriptional silencing or to mRNA degradation. Deregulation of the miRNA profile is found in many diseases including cancer [3]. Because most mammalian mRNAs have been shown to be targeted by miRNAs, disease-associated expression changes are mirrored by changes of the miRNA profiles [7,8]. As miRNAs can be purified from blood samples, it was suggested to utilize them as biomarkers for common illnesses, including cardiovascular diseases and cancer [9,10]. MiRNA expression profiles may be suitable as markers to evaluate the safety and efficacy of anticancer agents or to predict therapy response [11,12,13]
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