TY - JOUR
T1 - Black Raspberries Suppress Colorectal Cancer by Enhancing Smad4 Expression in Colonic Epithelium and Natural Killer Cells
AU - Huang, Yi Wen
AU - Lin, Chien Wei
AU - Pan, Pan
AU - Shan, Tianjiao
AU - Echeveste, Carla Elena
AU - Mo, Yue Yang
AU - Wang, Hsin Tzu
AU - Aldakkak, Mohammed
AU - Tsai, Susan
AU - Oshima, Kiyoko
AU - Yearsley, Martha
AU - Xiao, Jianbo
AU - Cao, Hui
AU - Sun, Chongde
AU - Du, Ming
AU - Bai, Weibin
AU - Yu, Jianhua
AU - Wang, Li Shu
N1 - Funding Information:
This work was supported by NIH grants CA148818 and USDA/ NIFA 2020-67017-30843 (to L-SW) and CA185301, AI129582, and NS106170 (to JY).
Publisher Copyright:
© Copyright © 2020 Huang, Lin, Pan, Shan, Echeveste, Mo, Wang, Aldakkak, Tsai, Oshima, Yearsley, Xiao, Cao, Sun, Du, Bai, Yu and Wang.
PY - 2020/12/14
Y1 - 2020/12/14
N2 - Innate immune cells in the tumor microenvironment have been proposed to control the transition from benign to malignant stages. In many cancers, increased infiltration of natural killer (NK) cells associates with good prognosis. Although the mechanisms that enable NK cells to restrain colorectal cancer (CRC) are unclear, the current study suggests the involvement of Smad4. We found suppressed Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Moreover, NK cell-specific Smad4 deletion promoted colon adenomas in DSS-treated ApcMin/+ mice and adenocarcinomas in AOM/DSS-treated mice. Other studies have shown that Smad4 loss or weak expression in colonic epithelium associates with poor survival in CRC patients. Therefore, targeting Smad4 in both colonic epithelium and NK cells could provide an excellent opportunity to manage CRC. Toward this end, we showed that dietary intervention with black raspberries (BRBs) increased Smad4 expression in colonic epithelium in patients with FAP or CRC and in the two CRC mouse models. Also, benzoate metabolites of BRBs, such as hippurate, upregulated Smad4 and Gzmb expression that might enhance the cytotoxicity of primary human NK cells. Of note, increased levels of hippurate is a metabolomic marker of a healthy gut microbiota in humans, and hippurate also has antitumor effects. In conclusion, our study suggests a new mechanism for the action of benzoate metabolites derived from plant-based foods. This mechanism could be exploited clinically to upregulate Smad4 in colonic epithelium and NK cells, thereby delaying CRC progression.
AB - Innate immune cells in the tumor microenvironment have been proposed to control the transition from benign to malignant stages. In many cancers, increased infiltration of natural killer (NK) cells associates with good prognosis. Although the mechanisms that enable NK cells to restrain colorectal cancer (CRC) are unclear, the current study suggests the involvement of Smad4. We found suppressed Smad4 expression in circulating NK cells of untreated metastatic CRC patients. Moreover, NK cell-specific Smad4 deletion promoted colon adenomas in DSS-treated ApcMin/+ mice and adenocarcinomas in AOM/DSS-treated mice. Other studies have shown that Smad4 loss or weak expression in colonic epithelium associates with poor survival in CRC patients. Therefore, targeting Smad4 in both colonic epithelium and NK cells could provide an excellent opportunity to manage CRC. Toward this end, we showed that dietary intervention with black raspberries (BRBs) increased Smad4 expression in colonic epithelium in patients with FAP or CRC and in the two CRC mouse models. Also, benzoate metabolites of BRBs, such as hippurate, upregulated Smad4 and Gzmb expression that might enhance the cytotoxicity of primary human NK cells. Of note, increased levels of hippurate is a metabolomic marker of a healthy gut microbiota in humans, and hippurate also has antitumor effects. In conclusion, our study suggests a new mechanism for the action of benzoate metabolites derived from plant-based foods. This mechanism could be exploited clinically to upregulate Smad4 in colonic epithelium and NK cells, thereby delaying CRC progression.
KW - Smad4
KW - black raspberries
KW - colorectal (colon) cancer
KW - human clinical trials
KW - natural killer cells
UR - http://www.scopus.com/inward/record.url?scp=85098236353&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098236353&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.570683
DO - 10.3389/fimmu.2020.570683
M3 - Article
C2 - 33424832
AN - SCOPUS:85098236353
VL - 11
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
M1 - 570683
ER -