Abstract
BackgroundThe long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) plays a crucial role in cancer progression, which is regulated by the interferon regulatory factor-1 (IRF1) and up-streaming Akt activation. The present study evaluated the chemopreventive effects of delphinidin-3-glucoside (Dp), a major anthocyanin present in pigmented fruits and vegetables, on breast carcinogenesis, and investigate the role of the Akt/HOTAIR signaling pathway.MethodsHuman breast epithelial cells MCF10A were treated with carcinogens (NNK and B[a]P) or co-treated with carcinogens plus Dp for 30 days. Then, the cancer-associated properties of the treated cells were evaluated to assess the carcinogenesis and the effects of Dp. HOTAIR levels were detected by qRT-PCR. The proteins expression was measured by western blots, immunofluorescence and immunohistochemistry. Xenografted tumors were made by implanting breast cancer cells MDA-MB-231-Luc-GFP in athymic mice. ChIP-qPCR analysis was used to detect the IRF1 binding to the HOTAIR promoter.ResultsCarcinogens treatment induces apparent carcinogenic transformation in MCF10A cells including reduced dependence on growth factors, anchorage-independent cell growth and aberrant wound-healing ability, which is effectively suppressed by Dp co-treatment. The level of HOTAIR significantly increases in a time-dependent manner during chronic breast carcinogenesis. Dp treatment down-regulates HOTAIR expression in breast carcinogenesis and breast cancer cells. Furthermore, Dp administration inhibits the growth of xenografted breast tumors in athymic mice, and decreases HOTAIR in vivo. Further studies showed that Dp represses Akt activation, promotes IRF1 expression and increases IRF1 binding to the HOTAIR promoter. Silence of IRF1 expression via transfecting cells with IRF1 siRNAs significantly reduced the effects of Dp on HOTAIR, resulting in decreased cytotoxic effects of Dp on breast cancer cells.ConclusionsThese data suggest the effective chemopreventive effect of Dp on breast carcinogenesis, in which down-regulation of HOTAIR plays a critical role.
Highlights
The long non-coding RNA HOX transcript antisense RNA (HOTAIR) plays a crucial role in cancer progression, which is regulated by the interferon regulatory factor-1 (IRF1) and up-streaming Akt activation
We evaluated the chemopreventive effects of delphinidin-3-glucoside (Dp), a major anthocyanin present in pigmented fruits and vegetables, on breast carcinogenesis and further investigated the role of the Akt/HOTAIR signaling pathway in the anti-cancer mechanism of Dp on breast cancer
Compared with carcinogens-treated cells (CarT), cells co-treated with carcinogens plus Dp (CarT-Dp) exhibited a significantly lower acquisition of reduced dependence on growth factors (RDGF) and anchorage-independent cell growth (AIG)
Summary
The long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) plays a crucial role in cancer progression, which is regulated by the interferon regulatory factor-1 (IRF1) and up-streaming Akt activation. The present study evaluated the chemopreventive effects of delphinidin-3-glucoside (Dp), a major anthocyanin present in pigmented fruits and vegetables, on breast carcinogenesis, and investigate the role of the Akt/HOTAIR signaling pathway. High fruit and vegetable consumption is associated with extensive beneficial health effects, which are partially due to the bioactivities of phytochemicals in plant-based foods. Yang et al BMC Cancer (2016) 16:423 natural polyphenol compounds that are widely found in berries, red grapes, purple potatoes, red cabbages, and many other pigmented fruits and vegetables. Over 400 anthocyanins have been identified in nature, and studies revealed that these polyphenol compounds have a number of bioactivities, including anti-oxidant, anti-inflammation, anti-atherosclerosis, and anti-cancer properties [6,7,8]
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