Black Raspberry Inhibits Oral Tumors in Mice Treated with the Tobacco Smoke Constituent Dibenzo(def,p)chrysene Via Genetic and Epigenetic Alterations

Abstract

We previously reported that the environmental pollutant and tobacco smoke constituent dibenzo [def,p]chrysene (DBP) induced DNA damage, altered DNA methylation and induced oral squamous cell carcinoma (OSCC) in mice. In the present study, we showed that 5% dietary black raspberry (BRB) significantly reduced (P < 0.05) the levels of DBP-DNA adducts in the mouse oral cavity with comparable effect to those of its constitutes. Thus, only BRB was selected to examine if aberrant DNA methylation induced by DBP can be altered by BRB. Using comparative genome-wide DNA methylation analysis, we identified 479 hypermethylated and 481 hypomethylated sites (q < 0.01, methylation difference >25%) between the oral tissues of mice treated with DBP and fed control diet or diet containing BRB. Among the 30 differential methylated sites (DMS) induced by DBP, we found DMS mapped to Fgf3, Qrich2, Rmdn2, and Cbarp were hypermethylated by BRB whereas hypomethylated by DBP at either the exact position or proximal sites; DMS mapped to Vamp3, Ppp1rB1, Pkm, and Zfp316 were hypomethylated by BRB but hypermethylated by DBP at proximal sites. In addition to Fgf3, 2 DMS mapped to Fgf4 and Fgf13 were hypermethylated by BRB; these fibroblast growth factors are involved in regulation of the epithelial-mesenchymal transition (EMT) pathway as identified by IPA. Moreover, BRB significantly reduced (P < 0.05) the tumor incidence from 70% to 46.7%. Taken together, the inhibitory effects of BRB on DNA damage combined with its effects on epigenetic alterations may account for BRB inhibition of oral tumorigenesis induced by DBP.Significance: We provided mechanistic insights that can account for the inhibition of oral tumors by BRB, which could serve as the framework for future chemopreventive trials for addicted smokers as well as non-or former smokers who are exposed to environmental carcinogens.

Wine Consumption and Oral Cavity Cancer: Friend or Foe, Two Faces of Janus

“…The environmental pollutant and tobacco smoke constituent dibenzo[def,p]chrysene (DBP) was used to induce OSCC in mice and to explore the effects of 5% dietary black raspberry. A reduction in the levels of DBP-DNA adducts in the mouse oral cavity with a comparable effect to those of its constituents was observed [130].…”

Black raspberry restores the expression of the tumor suppressor p120ctn in the oral cavity of mice treated with the carcinogen dibenzo[a,l]pyrene diol epoxide

“…We showed that BRB reduces oxidative stress in human oral leukoplakia cells [ 25 ]. Furthermore, we demonstrated that BRB inhibited OSCC induced by DBP or DBPDE via genetic and epigenetic alterations [ 15 , 16 ]. We also found that BRB was associated with a significant hypomethylation of the fibroblast growth factors (eg.…”

“…Inflammation is also induced in these mice and is exemplified by increases in Cox2 gene expression as well as several inflammatory cytokines such as Ccl22 and Cxcl10 [ 14 ]. Our team also demonstrated that feeding black raspberry (BRB) to both DBP and DBPDE treated mice inhibits tumor formation and altered several molecular targets in a manner consistent with its preventive/therapeutic action for HNSCC [ 15 , 16 ].…”

Berry chemoprevention: Do berries decrease the window of opportunity for tumorigenesis

“…The study reported that administration of a 5% BRB diet prior to carcinogen exposures resulted in fewer DNA adducts and abrogated tumor incidence from 93% to 66% (Chen et al, 2018). It was later reported that BRB-mediated reduction in oral mutagenesis could be attributed, in part, to epigenetics and hypermethylation of genes involved in epithelial-mesenchymal transition (Chen et al, 2020). These BRB-mediated metabolomic effects in oral cancer are further supported in a study by Knobloch et al (2019), using a chemically-induced model of oral cancer, (4-nitroquinoline-1oxide) (El-Bayoumy et al, 2017), whereby 6-week exposure to a 10% BRB diet inhibited enzymes fundamental for the metabolic pathway of glycolysis, thereby limiting nutrient availability for cancer cells (Knobloch et al, 2019).…”

“…The study reported that administration of a 5% BRB diet prior to carcinogen exposures resulted in fewer DNA adducts and abrogated tumor incidence from 93% to 66% (Chen et al., 2018). It was later reported that BRB‐mediated reduction in oral mutagenesis could be attributed, in part, to epigenetics and hypermethylation of genes involved in epithelial‐mesenchymal transition (Chen et al., 2020). These BRB‐mediated metabolomic effects in oral cancer are further supported in a study by Knobloch et al.…”