Modulation of genetic and epigenetic biomarkers of colorectal cancer in humans by black raspberries: a phase I pilot study.
OBJECTIVE
This study evaluated the effects of black raspberries (BRBs) on biomarkers of tumor development in the human colon and rectum including methylation of relevant tumor suppressor genes, cell proliferation, apoptosis, angiogenesis, and expression of Wnt pathway genes.


METHODS
Biopsies of adjacent normal tissues and colorectal adenocarcinomas were taken from 20 patients before and after oral consumption of BRB powder (60 g/d) for 1-9 weeks. Methylation status of promoter regions of five tumor suppressor genes was quantified. Protein expression of DNA methyltransferase 1 (DNMT1) and genes associated with cell proliferation, apoptosis, angiogenesis, and Wnt signaling were measured.


RESULTS
The methylation of three Wnt inhibitors, SFRP2, SFRP5, and WIF1, upstream genes in Wnt pathway, and PAX6a, a developmental regulator, was modulated in a protective direction by BRBs in normal tissues and in colorectal tumors only in patients who received BRB treatment for an average of 4 weeks, but not in all 20 patients with 1-9 weeks of BRB treatment. This was associated with decreased expression of DNMT1. BRBs modulated expression of genes associated with Wnt pathway, proliferation, apoptosis, and angiogenesis in a protective direction.


CONCLUSIONS
These data provide evidence of the ability of BRBs to demethylate tumor suppressor genes and to modulate other biomarkers of tumor development in the human colon and rectum. While demethylation of genes did not occur in colorectal tissues from all treated patients, the positive results with the secondary endpoints suggest that additional studies of BRBs for the prevention of colorectal cancer in humans now appear warranted.
Department of Internal Medicine, Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, Ohio 43240, USA. li-shu.wang@osumc.edu
Li-Shu
LS
Wang
Mark
M
Arnold
Yi-Wen
YW
Huang
Christine
C
Sardo
Claire
C
Seguin
Edward
E
Martin
Tim H-M
TH
Huang
Ken
K
Riedl
Steven
S
Schwartz
Wendy
W
Frankel
Dennis
D
Pearl
Yiqing
Y
Xu
John
J
Winston
Guang-Yu
GY
Yang
Gary
G
Stoner
D000328:Adult; D000369:Aged, 80 and over; D017209:Apoptosis; D014408:Biomarkers, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000178:diet therapy*; D019175:DNA Methylation; D005260:Female; D005638:Fruit; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D010865:Pilot Projects; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D051153:Wnt Proteins