Faculty Collaboration Database

Black Raspberries Suppress Colorectal Cancer by Enhancing Smad4 Expression in Colonic Epithelium and Natural Killer Cells. Front Immunol 2020;11:570683

Date

01/12/2021

Pubmed ID

33424832

Pubmed Central ID

PMC7793748

DOI

10.3389/fimmu.2020.570683

Scopus ID

2-s2.0-85098236353 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

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 Apc^Min/+ 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.

Author List

Huang YW, Lin CW, Pan P, Shan T, Echeveste CE, Mo YY, Wang HT, Aldakkak M, Tsai S, Oshima K, Yearsley M, Xiao J, Cao H, Sun C, Du M, Bai W, Yu J, Wang LS

Author

Chien-Wei Lin PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Adenoma
Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Agents
Cell Line, Tumor
Colon
Colorectal Neoplasms
Disease Models, Animal
Epithelial Cells
Female
Gene Expression Regulation, Neoplastic
Hippurates
Humans
Killer Cells, Natural
Male
Mice
Middle Aged
Rubus
Smad4 Protein
Tumor Microenvironment
Up-Regulation