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Delphinidin-3-glucoside suppresses breast carcinogenesis by inactivating the Akt/HOTAIR signaling pathway
Xiaohong Yang1, En Luo2, Xin Liu1
1Department of Public Health, Chengdu Medical College, Chengdu, China.
Background:
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.
Methods:
Human 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.
Results:
Carcinogens 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.
Conclusions:
These data suggest the effective chemopreventive effect of Dp on breast carcinogenesis, in which down-regulation of HOTAIR plays a critical role.
Insights
Delphinidin-3-glucoside (Dp) shows chemopreventive effects against breast cancer by down-regulating HOTAIR, a long non-coding RNA involved in cancer progression. Dp inhibits Akt activation and promotes IRF1, which suppresses HOTAIR, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Nutritional Science
Background:
- Long non-coding RNA (lncRNA) HOTAIR is implicated in cancer progression.
- Interferon regulatory factor-1 (IRF1) and Akt signaling pathway regulate HOTAIR.
- Delphinidin-3-glucoside (Dp), an anthocyanin, is investigated for chemopreventive properties.
Purpose of the Study:
- To evaluate the chemopreventive effects of Dp on breast carcinogenesis.
- To investigate the role of the Akt/HOTAIR signaling pathway in Dp's effects.
- To determine Dp's impact on IRF1 and HOTAIR expression.
Main Methods:
- MCF10A cells treated with carcinogens and Dp.
- HOTAIR expression analyzed by qRT-PCR.
- Protein expression via western blots, immunofluorescence, and immunohistochemistry.
- Xenografted tumor models in athymic mice.
- ChIP-qPCR to assess IRF1 binding to the HOTAIR promoter.
Main Results:
- Dp suppressed carcinogen-induced cell transformation, including reduced growth factor dependence and anchorage-independent growth.
- Dp treatment significantly down-regulated HOTAIR expression in vitro and in vivo.
- Dp inhibited xenografted tumor growth and decreased HOTAIR levels.
- Dp repressed Akt activation, increased IRF1 expression, and enhanced IRF1 binding to the HOTAIR promoter.
- IRF1 knockdown diminished Dp's effects on HOTAIR and its cytotoxic impact.
Conclusions:
- Dp exhibits effective chemopreventive effects against breast carcinogenesis.
- Down-regulation of HOTAIR is a critical mechanism in Dp's chemopreventive action.
- The Akt/IRF1/HOTAIR pathway is a key target for Dp's therapeutic potential.
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