Molecular nutrition & food research. 2012 Nov; 56(11): 1617-1626

Interaction effects between genes involved in the AKT signaling pathway and phytoestrogens in gastric carcinogenesis: A nested case-control study from the Korean Multi-Center Cancer Cohort.

Jae Jeong Yang1,2, Lisa Y. Cho1,2, Kwang-Pil Ko3, Seung Hyun Ma1,2, Aesun Shin4,Bo Youl Choi5, Dong Soo Han6, Kyu Sang Song7, Yong Sung Kim8, Soung-Hoon Chang9, Hai-Rim Shin3,10, Daehee Kang1,2,11, Keun-Young Yoo1 and Sue K. Park 1,2,11

1 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
2 Cancer Research Institute, Seoul National University, Seoul, Korea
3 Department of Preventive Medicine, Gachon University of Medicine and Science, Incheon, Korea
4 Molecular Epidemiology Branch, Research Institute, National Cancer Center, Goyang, Korea
5 Department of Preventive medicine, Hanyang University College of Medicine, Seoul, Korea
6 Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
7 Department of Pathology, Chungnam National University College of Medicine, Daejeon, Korea
8 Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
9 Department of Preventive Medicine, Konkuk University, Chungju, Korea
10Non Communicable Diseases and Health Promotion, World Health Organization, Western Pacific Regional Office,
Manila, Philippines
11 Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea



Scope: To investigate whether genes involved in AKT/nuclear factor kappa B signaling and/or gene-environment interactions between the genes and phytoestrogens may be susceptible factors for gastric cancer.

Methods and results: The representative single nucleotide polymorphisms (SNPs) identified during the primary analysis (screening a total of 622 SNPs within ± 5 kbp of the 51 target gene locations) were further investigated in 317 matched case-control sets. The summary odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer were calculated. Interaction effects between the SNPs and phytoestrogen biomarkers (genistein, daidzein, equol, and enterolactone) were computed. CDK1 rs4145643, FAS rs6586161, and FAS rs1468063 in the AKT signaling pathway presented significant genetic effects on gastric cancer (OR = 0.81 (95% CI: 0.66-0.99) for CDK1 rs4145643; OR = 1.27 (95% CI: 1.03–1.58) for FAS rs6586161; OR = 1.29 (95% CI: 1.03–1.56) for FAS rs1468063; Cochran Q statistics > 0.10). Risk alleles of FAS rs6586161, FAS rs1468063, MAP3K1 rs16886448, and MAP3K1 rs252902 showed significant interaction effects with enterolactone (pinteraction < 0.05).

Conclusion: CDK1 and FAS genes involved in AKT signaling and influenced by anticarcinogenic property of phytoestrogens can play a role as susceptible genetic factors in gastric carcinogenesis. FAS and MAP3K1 genes significantly interact with enterolactone, thereby modifying the individual’s risk for gastric cancer

PMID: 23042672



Phytoestrogens are compounds derived from plants and can mimic the function of the female sex hormone. Several studies about putative effects of phytoestrogens to the hormone-specific cancers have been progressed and some research reported that phytoestrogens may reduce the risk of non-hormone specific gastric, lung, colorectal cancers. Our previous study also proposed that significant interaction between phytoestrogens and some genetic factors involved in cytotoxin-associated gene A (CagA) signaling pathway modifies the risk of gastric cancer. Also it its known that phytoestrogens can inhibit the phosphatidylinositol-3-kinase(PI3K)/AKT and nuclear factor kappa B(NF-κB) signaling involved in gastric carcinogenesis. Phytoestrogen’s inhibition to the AKT/NF-κB signal transduction pathway may affect cell growth and/or survival considering that PI3K/AKT and NF-κB signaling pathways regulate cell growth, proliferation, migration, differentiation, apoptosis. Contrary to phytoestrogen, Helicobacter pylori can activate PI3K/AKT and NF-κB signal transductions and cause mucosal inflammation.

We analyzed that (ⅰ)phytoestrogens influence on genes involved in AKT/NF-κB signaling pathways and (ⅱ)gene-environmental interaction between phytoestrogens and genetic variants on the AKT/NF-κB pathways might be susceptible factor for gastric cancer. In the present study, CDK1 rs4145643, FAS rs6586161, and FAS rs1468063 which are involved in the AKT signaling pathway presented a significant association with gastric carcinogenesis without heterogeneity. The gene-environmental interaction between representative SNPs and phytoestrogens was only observed in enterolactone among four phytoestrogen biomarkers.

CDK1 is taking charge for the cell cycle and its aberrant activity is associated with cell-cycle defects which are related to the development of tumor. Although the biological mechanism of CDK1’s activity is still unclear, given the CDK1’s major role throughout the cell-cycle progression, genetic polymorphisms of CDK1 may play a role as susceptible genetic factors in cancer development, especially that of gastric cancer.

FAS which is known as representative death receptor modulates programed cell death, homeostasis in immune system, and carcinogenic activity. Considering that apoptosis in gastric epithelial cells by FAS may affect the development of gastric cancer, FAS can be a risk factor of gastric cancer and may induce individual genetic susceptibility to oncogenesis.

Enterolactone-mediated inhibition to AKT phosphorylation was proposed and such inhibition is one of the most frequent conversions in human cancers. Enterolactone also inhibits insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R), its upstream targets. Our present research showed that interaction between FAS genes and enterolatone modifies gastric cancer risk. Such results support that FAS may interfere in enterolactone’s activity and modify the risk of gastric cancer. Despite of inconclusive results, association between MAP3K1 genetic polymorphism and enterolactone should be treated as speculative risk modifiers in development of gastric cancer. MAP3K1 genetic polymorphism may interfere in enterolatone’s protective effects on gastric cancer taking account of NF-κB activity which can modulate cellular activities such as immune systems, inflammatory responses, cytokine/chemokine production, apoptosis.



This study was supported by a grant from Korean Foundation for Cancer Research (KFCR-CB-2013-01).

The authors have declared no conflict of interest.

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