Epigenetic Alteration Of Wnt-associated Tumor Suppressor Genes In Colorectal Cancer By Black Raspberry Polyphenols

Colorectal cancer is one of the common malignant tumor, still the third most commonly diagnosed cancer worldwide. The occurrence of tumor is generally considered to be due to changes in the genetic and epigenetic level. DNA methylation is the most common epigenetic phenomenon and inhibits transcription complex binding to DNA, silencing functional genes. DNA methylation is a reversible process. Hypermethylation of tumor suppressor genes can be altered by acting on the reversible process. Current thinking is that the development of molecular drug targeting protein is a new research direction treating colorectal cancer.Black raspberries (BRB) are a natural food enriched in protective anti-oxidant and anti-inflammatory chemicals such as ellagic acid, ferulic acid, quercetin, and anthocyanins. Previous studies have demonstrated that dietary freeze-dried BRB reduce intestinal tumor incidence and tumor development in transgenic mouse models. Data from a pilot clinical trial in colorectal cancer patients demonstrated that the chemopreventive role of BRB on colorectal tumors was associated with demethylation of relevant tumor suppressor genes. The study was designed to elucidate the roles of BRB and their bioactive components on epigenetic alternations in tumor suppressor genes associated with the Wnt-signaling pathway, both in an animal model of colitis-induced colorectal cancer and in cancer cells in vivo and in vitro. As the results:(1) In vivo, the hypermethylation status of Wnt-associated tumor suppressor genes SFRP2, WIF1 were altered by black raspberry polyphenols, which also down-regulated β-catenin protein and DNA methyltransferases (DNMTs) DNMT1, DNMT3A, DNMT3B.Therefore, the results showed that black raspberry polyphenols inhibited colorectal cancer by down-regulating DNMTs then inhibiting DNA methylation and preventing the silence of SFRP2, WIF1.(2) In vitro, the proliferations of human colorectal cancer LoVo, HCT-116 were inhibited by black raspberry polyphenols. The hypermethylation status of Wnt-associated tumor suppressor genes SFRP2, WIF1 were altered by black raspberry polyphenols, which also down-regulated β-catenin, cyclins, matrix metalloproteinases (MMPs) and up-regulated anti apoptotic protein, E-cadherin proteins level.In conclusion, one of the mechanisms inhibiting colorectal cancer of black raspberry polyphenols is down-regulating the hypermethylation of promoters of SFRP2, WIF1 by decreasing the DNMTs and then reducing β-catenin. In addition, black raspberry polyphenols decreased the development and metastasis by other apoptosis, metastasis signaling pathway proteins.Based on the above experimental results, the study of black raspberry polyphenols on preventing tumor has the vital significance. Black raspberry polyphenols, as a new type of preparation, has great potential on prevention and treatment of colorectal cancer. In the long run, it has better clinical application prospect.