7-Difluoromethoxyl-5,4'-di-n-octyl genistein inhibits the stem-like characteristics of gastric cancer stem-like cells and reverses the phenotype of epithelial-mesenchymal transition in gastric cancer cells.
7-Difluoromethoxyl-5,4'-di-n-octyl genistein (DFOG), a novel synthetic genistein analogue, exerts anticarcinogenic activity in several types of cancers, including gastric cancer. Accumulating evidence in recent years strongly indicates the existence of cancer stem cells in gastric cancer. The objective of the present study was to investigate whether DFOG inhibits the stemness and reverses the epithelial-mesenchymal transition (EMT) phenotype of gastric cancer stem-like cells (GCSLCs) derived from human gastric cancer SGC-7901 cells and to identify its potential mechanism. Sphere-forming cells (SFCs) from the SGC-7901 cells possessed the properties of GCSLCs. DFOG preferentially inhibited self-renewal, cell migration and cell invasion, and downregulated the expression of stem cell biomarkers in a dose-dependent manner. At the molecular level, these effects were accompanied by the downregulation of forkhead box M1 (FoxM1). Meanwhile, FoxM1 siRNA transfection was able to synergize the inhibition of expression of FoxM1 and Twist1 induced by DFOG in GCSLCs. In addition, we found that DFOG treatment decreased the expression of N-cadherin and increased the expression of E-cadherin. More importantly, FoxM1 siRNA transfection cooperated with DFOG to suppress the self-renewal capacity, cell migration and cell invasion, and downregulated the expression of CD133, CD44, ALDH1, and also regulated the expression of N-cadherin and E-cadherin. These findings showed that DFOG inhibited the stem-like characteristics of GCSLCs and reversed the EMT phenotype by modulation of FoxM1 and further decreased Twist1 expression. Our results provide a further rationale and experimental basis for using DFOG to improve the efficacy of treatment for patients with gastric cancer.
Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
Xiaozheng
X
Cao
Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
Kaiqun
K
Ren
Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
Zhengwei
Z
Song
Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
Duo
D
Li
Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
Meifang
M
Quan
Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
Yu
Y
Zheng
Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
Jianguo
J
Cao
School of Pharmaceutical Sciences and Molecular Imaging Research Center, Central South University, Changsha, Hunan 410013, P.R. China.
Wenbin
W
Zeng
Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China.
Hui
H
Zou
D000071916:AC133 Antigen / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D000072278:Forkhead Box Protein M1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019833:Genistein / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014162:Transfection / Q000379:methods; D051879:Twist-Related Protein 1 / Q000378:metabolism
C579741:7-difluoromethoxyl-5,4'-di-n-octylgenistein; D000071916:AC133 Antigen; C497483:CD44 protein, human; D015820:Cadherins; D000072278:Forkhead Box Protein M1; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D034741:RNA, Small Interfering; D051879:Twist-Related Protein 1; D019833:Genistein; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase