title: Delphinidin-3-glucoside suppresses breast carcinogenesis by inactivating the Akt/HOTAIR signaling pathway.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  These data suggest the effective chemopreventive effect of Dp on breast carcinogenesis, in which down-regulation of HOTAIR plays a critical role.
authors.affiliation: Department of Public Health, Chengdu Medical College, Chengdu, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of General Surgery, The Fifth People's Hospital of Chengdu, Chengdu, China.
authors.forename: En
authors.initials: E
authors.lastname: Luo
authors.affiliation: Department of Public Health, Chengdu Medical College, Chengdu, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Public Health, Chengdu Medical College, Chengdu, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Public Health, Chengdu Medical College, Chengdu, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Public Health, Chengdu Medical College, Chengdu, China. xiaopeng967@sohu.com.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Peng
mesh_terms: D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009602:Nitrosamines / Q000633:toxicity; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000872:Anthocyanins; D005960:Glucosides; C561566:HOTAIR long untranslated RNA, human; D009602:Nitrosamines; D062085:RNA, Long Noncoding; C494120:delphinidin 3-O-glucopyranoside; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D051057:Proto-Oncogene Proteins c-akt
keywords: Anthocyanin; Breast cancer; Carcinogenesis; HOTAIR; lncRNAs