Wnt4 Research Articles

Therapeutic Effect of Calcimimetics on Osteoclast-Osteoblast Crosslink in Chronic Kidney Disease and Mineral Bone Disease.

We have previously demonstrated calcimimetics optimize the balance between osteoclastic bone resorption and osteoblastic mineralization through upregulating Wingless and int-1 (Wnt) signaling pathways in the mouse and cell model. Nonetheless, definitive human data are unavailable concerning therapeutic effects of Cinacalcet on chronic kidney disease and mineral bone disease (CKD-MBD) and osteoclast–osteoblast interaction. We aim to investigate whether Cinacalcet therapy improves bone mineral density (BMD) through optimizing osteocytic homeostasis in a human model. Hemodialysis patients with persistently high intact parathyroid hormone (iPTH) levels > 300 pg/mL for more than 3 months were included and received fixed dose Cinacalcet (25 mg/day, orally) for 6 months. Bone markers presenting osteoclast–osteoblast communication were evaluated at baseline, the 3rd and the 6th month. Eighty percent of study patients were responding to Cinacalcet treatment, capable of improving BMD, T score and Z score (16.4%, 20.7% and 11.1%, respectively). A significant correlation between BMD improvement and iPTH changes was noted (r = −0.26, p < 0.01). Nonetheless, baseline lower iPTH level was associated with better responsiveness to Cinacalcet therapy. Sclerostin, an inhibitor of canonical Wnt/β-catenin signaling, was decreased from 127.3 ± 102.3 pg/mL to 57.9 ± 33.6 pg/mL. Furthermore, Wnt-10b/Wnt 16 expressions were increased from 12.4 ± 24.2/166.6 ± 73.3 pg/mL to 33.8 ± 2.1/217.3 ± 62.6 pg/mL. Notably, procollagen type I amino-terminal propeptide (PINP), a marker of bone formation and osteoblastic activity, was increased from baseline 0.9 ± 0.4 pg/mL to 91.4 ± 42.3 pg/mL. In contrast, tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), a marker of osteoclast activity, was decreased from baseline 16.5 ± 0.4 mIU/mL to 7.7 ± 2.2 mIU/mL. Moreover, C-reactive protein levels were suppressed from 2.5 ± 0.6 to 0.8 ± 0.5 mg/L, suggesting the systemic inflammatory burden may be benefited after optimizing the parathyroid–bone axis. In conclusion, beyond iPTH suppression, our human model suggests Cinacalcet intensifies BMD through inhibiting sclerostin expression and upregulating Wnt-10b/Wnt 16 signaling that activates osteoblastic bone formation and inhibits osteoclastic bone resorption and inflammation. From the perspective of translation to humans, this research trial brings a meaningful insight into the osteoblast–osteoclast homeostasis in Cinacalcet therapy for CKD-MBD.

Expression of apoptosis and myogenesis related genes during prenatal life in two divergent breeds of pigs

We aimed to evaluate apoptosis and myogenesis related genes expression in embryos and fetuses from two divergent genetic groups of pigs: Piau breed and a commercial line. Thirty females (15 Piau and 15 commercial line) were selected at 120 days of age. Estrous cycle was observed and on the third estrus females were considered sexually mature. Gilts were inseminated with semen from males of the respective breed. Three females from each breed were slaughtered at five different gestational ages: 15, 30, 45, 60 and 90 days. Whole embryos (15 and 30 d) and samples of longissimus dorsi muscle from fetuses (45, 60 and 90 d) were collected for RNA extraction. Expression of apoptosis and myogenesis related genes (BAX, BCL2, FGF4, IHH, HHIP, SHH, SOX2, WNT1 and WNT4) were evaluated by quantitative real time PCR. There was significant effect of interaction between breeds and gestational ages for all genes evaluated (P < 0.05). The BCL2 gene expression differed throughout pregnancy in Piau group with lower expression on day 15. The IHH gene expression throughout pregnancy was lower on days 15 and 60 in Piau group and lower on day 90 in commercial line group; and the SHH gene expression throughout pregnancy was higher on day 30 and lower on day 60 in Piau group and lower on day 45 in commercial group. The WNT1 gene expression along pregnancy was lower on day 15 and higher on days 30 and 45 in Piau group, and it was higher on day 30 than days 15 and 60 in commercial group. WNT4 gene expression throughout pregnancy was lower on day 15 in Piau group, and it was lower on day 30 in commercial pigs. Piau group presented higher expression of the FGF4 gene on days 45, 60 and 90, and commercial group showed higher expression on day 15 and 90. SOX2 gene expression was lower on day 15 in Piau pigs and it was constant throughout pregnancy in commercial group. Overall, the expression of IHH, SHH, WNT1, WNT4 and FGF4 genes were higher in commercial than Piau pigs on day 15, besides expression of BCL2 gene in Piau embryos was lower on day 15; these results might indicate that the muscle precursor cells are allowed to proliferate for a longer time in commercial than in Piau embryos by the balance of proliferative and apoptotic genes. Therefore, the expression differential between breeds can stimulate proliferation and differentiation of cells in different ways, explaining the postnatal differences in the muscularity between pigs from Piau breed and a commercial line.

Differential gene expression of Thy0517 cells in thymoma after down-regulation of Wnt4 and fork head gene family protein N1 gene

Differential gene expression of Thy0517 cells in thymoma after down-regulation of Wnt4 and fork head gene family protein N1 gene

Whole-genome expression analysis of synovial fibroblasts in rheumatoid arthritis

Objective To identify the crucial gene implicated in rheumatoid arthritis (RA) pathogenesis by comparing microarray-based gene expression profiles of synovial fibroblast in arthritis patients and that in control. Methods The public da-tasets were obtained from NCBI GEO and EBI ArrayExpress. The qualified microarray-based gene expression profiles were inte-grated and normalized using the method implemented in GeneSpring software. Furthermore, the differentially expressed genes (DEGs) were identified using significance analysis of microarrays (SAM) method. The online tool DAVID and STRING were ap-plied to conduct the enrichment analysis and gene product interaction analysis respectively. Results There were two datasets that were qualified and analyzed in the present study. A total of 336 significant DEGs were identified by comparing the whole-ge-nome gene expression profiles from synovial fibroblast of RA patients and control group. Among these DEGs, 261 were significant-ly downregulated and 75 upregulated. About 13.6% of the downregulated genes were associated with extracellular matrix degrada-tion. The COL9A3 and COL4A5, indispensable component of hyaline cartilage and basement membrane respectively, were signifi-cantly downregulated, as well as genes in WNT family, including WNT2, WNT11, and WNT16. In contrast, matrix metalloprotein-ase 13 (MMP13) was found to be significantly upregulated in RA patients. MMP13 is a matrix metallopeptidase that degrade extra-cellular matrix and hyaline cartilage, and it could possibly interact with other proteins to regulate morphogenesis. Conclusion Molecular mechanisms underlying RA pathogenesis were investigated by analyzing the public datasets. A few genes that associat-ed with extracellular matrix degradation, construction and regulation, including MMP13, WNT2, WNT11, WNT16, COL9A3 and COL4A5, could be regarded as therapeutic targets in RA treatment. Key words: Arthritis, rheumatoid; Knee joint; Synovial Membrane; Fibroblasts; Gene expression profiling

WNT16 is up-regulated in the joint following inflammation

WNT16 is up-regulated in the joint following inflammation

Regulatory mechanism of Runt related transcription factor 2 in fracture healing by salidrosid

Objective To compare and evaluate the differences of curative effects and biological mechanisms underlying the posttraumatic bone healing, as well as the study of the regulation of Runt related transcription factor 2 (Runx2) signal pathway mechanism of osteogenesis by using Salidroside. Methods To establish an close osteotomy model of SD rats. 40 rats divide into experimental group and control group. Using microCT to evaluate and compare the curative efficacy about the posttraumatic bone healing. Using the method of enzyme linked immunosorbent assay (ELISA), the serum concentrations of alkaline phosphatase (ALP), osteoprotegerin (OPG) were assessed. Using the method of real-time quantitative polymerase chain reaction (Real-time PCR), the mRNA expression levels of Runx2, hypoxia inducible factor (HIF) 2A, Wnt4, Wnt10b, β-catenin, glycogen synthase kinase (GSK)-3β, T-cell factor (TCF)-1 in callus tissue were determined. Results At 2 and 4 weeks after surgery, the callus bone structural parameters of microCT were significantly improved in experimental group compared to that of control group (P<0.05). In addition, at weeks 2 and 4 after surgery, the mRNA expressions of Runx2 (2 w: 1.83±0.11, 4 w: 2.23±0.11), HIF2A (2 w: 1.37±0.12, 4 w: 1.50±0.12), Wnt4 (2 w: 1.78±0.10, 4 w: 1.66±0.11), Wnt10b (2 w: 1.89±0.12, 4 w: 1.92±0.13), β-catenin (2 w: 1.65±0.08, 4 w: 1.72±0.10) were significantly increased, whereas the mRNA expressions of GSK-3β (2 w: 0.61±0.08, 4 w: 0.56±0.09) were significantly decreased (P<0.05). The serum concentrations of ALP [2 w: (335.34±9.23) IU/L, 4 w: (312.45±10.56) IU/L]P, OPG [2 w: (40.02±2.90) IU/L, 4 w: (45.56±3.20) pg/ml] were significantly increased (P<0.05). Conclusion Compared with the Control group, the Salidroside group make an effect to fracture healing. Key words: Salidroside; Runt related transcription factor 2 signal pathway; Osteogenesis regulation

Aberrant levels of Wnt/β-catenin pathway components in a rat model of endometriosis.

Endometriosis is a benign gynecological disease affecting approximately 10-15% of women of reproductive age and 25-50% of all infertile women. It is characterized by the presence of glands and/or endometrial stroma outside the uterine cavity. Angiogenesis is a crucial process for the development and maintenance of endometriotic lesions. The Wnt/β-catenin pathway is a major promoter of angiogenesis in both physiological and pathological conditions. In the present study, we evaluated the expression of molecules related to the Wnt/β-catenin pathway in a rat model of peritoneal endometriosis. mRNA analyses showed significantly increased expression of Wnt4 and Wnt7b and decreased expression of Gsk3beta and E-cadherin in endometriotic lesions. However, there were no differences in β-catenin and Fzd2 mRNA expression. In addition, we observed a significant increase of nuclear β-catenin in endometriotic lesions, a hallmark of Wnt/ β-catenin pathway activation. Stromal β-catenin staining was found in 45.4% of endometrial tissues and 77.8% of endometriotic lesions. β-catenin nuclear localization was found in 18.2% of the endometrial tissues and 33.3% of endometriotic lesions. Finally, the expression of galectin-3, a regulator of this pathway, was increased in endometriosis. In summary, this pattern of Wnt/β-catenin components expression suggests an increased activity of this pathway in endometriosis.

AB139. Studies on the mechanism of testicular dysfunction in the early stage of a streptozotocin induced diabetic rat model

Streptozotocin (STZ) induced diabetic model has been widely used to study the effects of diabetes mellitus (DM) on male infertility, but it remains unclear whether the responses in this model are due to hyperglycemia or STZ per se. This study was designed to investigate the mechanism of STZ on testicular dysfunction. In the present study, sperm characteristics, serum testosterone, steroidogenic enzymes (StAR and 3β-HSD), and the vimentin apical extension of sertoli cells decreased significantly in the STZ group compared with those in the normal controls (P<0.05), while Johnsen’s score, testicular lipid peroxidation, spermatogenic cell apoptosis, and the expressions of NF-κB and Wnt4 significantly increased (P<0.05). Insulin replacement mainly restored the decreased serum testosterone and steroidogenic enzymes, but not other parameters. The results indicated that spermatogenic dysfunction in the early stage of STZ-induced diabetic rats was due to direct STZ cytotoxity to sertoli cells, which could be regulated by Wnt4 and NF-κB, while steroidogenic dysfunction might be a direct or indirect consequence of insulin deficiency. The results suggested that STZ-induced diabetic model, at least in the early stage, is not suitable to study the diabetes-related spermatogenic dysfunction.

WNT1 for the skeleton

WNT1 for the skeleton

Effects of 1, 25 (OH)2D3 on bleomycin-induced pulmonary fibrosis in mice

To observe the effects of 1, 25(OH)2D3 on bleomycin-induced pulmonary fibrosis in mice and to explore its mechanisms. Ninety male C57BL/6 mice, 6 to 8 weeks old, were randomly divided into 3 groups according to the table of random numbers: a control group, a model group and a treatment group(n = 30 each). Bleomycin was injected to the mice in the latter 2 groups by single intratracheal injection to duplicate the pulmonary fibrosis model, while the control group was injected with saline. From the next day, the mice in the treatment group received 1, 25 (OH) 2D3 (0.5 µg·kg(-1)·d(-1)) diluted in olive oil by gavage daily, while the other groups were treated with equivalent olive oil. Ten mice in each group were killed randomly on day 14, 21 and 28 after surgery respectively. Pulmonary alveolitis and fibrosis were evaluated by using hematoxylin-eosin and Masson stain method. The content of hydroxyproline was measured by acid hydrolysis method. The mRNA levels of collagen1α1, α-SMA, Wnt3a, Wnt4, and Wnt7a in the lung tissues were measured by real-time RT-PCR, while the protein expression of α-SMA and β-catenin were assessed by immunohistochemistry. Pulmonary alveolitis at day 14, 21 and fibrosis at day14, 21, 28 in the treatment group were remarkably reduced compared to the model group (all P < 0.05). Compared with the model group, the treatment group showed decreased content of hydroxyproline, decreased mRNA levels of collagen1α1, α-SMA, Wnt3a, Wnt4 and decreased protein expression of α-SMA and β-catenin at the 3 time points (all P < 0.05). The content of hydroxyproline and the mRNA levels of collagen1α1, α-SMA, Wnt3a, Wnt4, Wnt7a in the treatment group at 28 d were 0.67 ± 0.14, 1.66 ± 0.34, 1.37 ± 0.41, 1.43 ± 0.27, 1.29 ± 0.19, 1.18 ± 0.20, respectively, all of which were significantly lower than those in the model group (1.10 ± 0.16, 3.50 ± 0.74, 2.68 ± 0.61, 2.60 ± 0.58, 2.23 ± 0.45, 1.93 ± 0.36, respectively). Protein expression of α-SMA and β-catenin in the treatment group were 0.44 ± 0.13 and 0.25 ± 0.05, respectively, which were also significantly lower than those of the model group(0.98 ± 0.20, 0.58 ± 0.06, respectively). 1, 25 (OH) 2D3 was shown to reduce pulmonary fibrosis induced by bleomycin in mice, and its mechanisms might be associated with Wnt signaling suppression.

Dynamic changes of expression of Wnt4 in pituitary adenomas tissue in rats

Objective To observe the dynamic changes of Wnt4 expression in pituitary tissue fiom rats with pituitary adenoma models induced by diethylstibestrol (Des),and probe into the possible mechanism of Wnt4 signal transduction pathway in tumorigenesis and development of pituitary adenomas.Methods Sixty Wistar rats were randomly divided into DES-treated group (Des),arachis (o)il-treated control group (AO) and feign-treated control group (FT).Behavior changes and body weight were recorded.Ten rats in DES-treated group and 5 in each control group were sacrificed after 4,8 and 12 weeks,respectively.The weight,histological and morphological changes of the pituitary gland,serum prolactin (PRL) level,and expression of Wnt4 were detected.Results Tumor formation rate was 30％,90％ and 100％,and the Wnt4 positive scores was 5.80 ±3.32,8.40 ±2.22 and 9.70 ± 1.64 at 4th,8th and 12th week in Des group,respectively.The Wnt4 positive scores in control group were 0.80 ± 0.83,1.40 ± 1.14 and 1.20 ± 0.83 at 4th,8th and 12th week,respectively.Wnt4 expression was significantly higher in Des group than in other groups (P ＜ 0.05),and had acending trend along with the treating time of Des.Conclusion Pituitary tumor model induced by Des in Wistar rats was a stable and convenient pituitary tumor model.Wnt4 signal transduction pathway may play an important role in tumorigenesis and development of pituitary adenomas. Key words: Pituitary adenoma ; Wnt4 ; Signaling transduction pathway ; Model, animal

Identification and directed differentiation of nuclear transfer embryonic stem cells

Objective To explore the effects of metanephric cell microenvironment inducing differentiation of embryonic stem cells (ESCs) into renal cells.Methods We constructed mouse reconstructed embryos.The nuclear transfer embryonic stem cells (ntESCs) like colonies were identified by characterized morphology,alkaline phosphatase activity assay,and cell karyotypes examination.The differentiation was examined both in vivo and in vitro.The ntESCs were induced to form embryoid bodies by suspension culture.The cells from nuclear transfer embryoid bodies (ntEBs) were co-cultured with metanephric mesenchymal cells.Differences in mRNA expression (WT-1,Wnt-4,pax-2,c-Ret,podocalyxin and Nephrin) between the induced ntEBs and the controls were detected by reverse transcription-polymerase chain reaction (RT-PCR).The proteins of Pax-2 and WT-1 in the induced ntEBs and the controls were analyzed by immunofluorescence.Results Most of ntESCs had typical characteristics of mouse embryonic stem cells.The genes related to kidney development were expressed in the ntEBs cells,and the mRNA expression of WT-1,Wnt-4,pax-2,c-Ret,podocalyxin and Nephrin in the induced ntEBs was positive.Those in control groups were negative.The fluorescence intensity of Pax-2 in the induced ntEBs was high ( ++ ) ; The fluorescence intensity of WT-1 in the induced ntEBs was higher ( + ) than that in the control group ( ± ).Conclusion Metanephric cell microenvironment promotes differentiation of ntESCs which cultured from nuclear transfer blastocysts into renal cells. Key words: Nuclear transfer; Embryonic stem cells; Renal cells

Effects of fulvestrant on biological activity and Wnt expression in rat GH3 cells.

The present study investigated the influence of anti-estrogen treatment (fulvestrant) on pituitary adenoma cell line GH3 biological activity, the estrogen receptor α pathway, the WnT pathway, and mechanisms of decreased Wnt inhibitory factor-1 expression in GH3 cells. Results showed that fulvestrant suppressed GH3 cell proliferation and reduced hormone secretion in a dose-dependent manner. Estrogen receptor α and Wnt4 expression decreased, but Wnt inhibitory factor-1 expression increased in a dose-dependent manner following fulvestrant treatment, and β-catenin expression remained unchanged. Inhibitors of DNA methylation and histone modification upregulated Wnt inhibitory factor-1 expression. Results suggested that fulvestrant suppressed biological activity of GH3 cells via the estrogen receptor α and Wnt pathways. These results suggested that decreased Wnt inhibitory factor-1 expression in GH3 cells played a role in epigenetic mechanisms. Anti-estrogen therapies could provide novel treatments for growth hormone adenomas.

Mechanism of intracellular signaling transduction through p-catenin during fracture healing

Objective To observe the changes of p-catenin during fracture repair and explore the mechanism of signaling transduction through p-catenin during fracture repair. Methods Mice were randomly divided into three groups,and the animal models of tibia fracture were established. Western blot analysis was employed for detecting the p-catenin expression at different time points during fracture repair. Quantitative RT-PCR was used to detect Wnt ligmants and their receptors during fracture repair to understand whether signaling transduction through p-catenin during fracture healing was directly regulated by Wnts. Histomorphometric measurements were used to observe the effect of Dkk-1 on fracture repair for further understanding function of p-catenin. Results p-catenin level was low in intact bone tissue,but highly expressed during the entire period of fracture repair. Callus samples from animals treated with Ad-Dkkl exhibited a greater reduction of β-catenin level. Wnt-4, Wnt5b and their receptors Fz-1 and Lrp-6 were upregulated during fracture healing. In Dkk-1 and contror groups, using histomorphometric measurements, there was substantial reduction of callus parameters. Bone and cartilage volume as a percentage of total callus tissue volume,trabecular thickness,trabecular number (per mm) and trabecular separation (μm) in Dkk-1 and contror groups were (11.33 ± 2. 52)%/(35. 67 ± 3.06)% , (14. 33 ± 2 51)%/(47. 33 ± 4.04)%,(720.00 ±77.70) μm/(189.33 ±83.36)μm,13.67 ±2.05/32.33 ±2.62,(1.25 ±0.96) μm/ (4.00 ± 0.82) ujn respectively (P<0.01). Conclusion p-catenin may play a key signaling role during fracture healing. The therapy to activate p-catenin could be used to enhance fracture repair. Key words: Fracture healing; p-catenin; Wnts; Signaling transduction

Potential role of Wnt signaling pathway in epidermal cell dedifferentiation under traumatic microenvironment

Objective To investigate the inductive role of traumatic microenvironment in dedifferentiation of epidermal cells and explore the potential role of Wnt signaling pathway in this biological process. Methods The sheets of human foreskin were digested overnight after removal of adipose tissue, and then the epidermis was separated from the dermis. The separated epidermis sheets were repeatedly adhered to type Ⅳ collagen and flushed to remove the epidermal stem cells. The obtained epidermis sheets were transplanted onto the full-thickness skin wounds on the back of BALB/c nude mice, five days after which the cell lineage was evaluated by immunohistochemistry and the expressions of Wnts and downstream components in the grafted epidermal sheets examined by RT-PCR and Western blot. Results The cells in the basal layer of full-thickness epidermal sheets were positive for CK19 and β1 integrin and negative for CK10. While the cells in uhrathin epidermal sheets treated with type Ⅳ collagen were fully positive for CK10. Five days after transplantation of the ultrathin epidermal sheets, cells negative for CK10 but positive for CK19 and β1 integrin emerged at the wound-neighboring side of the skin grafts. At the same time, the expressions of Wnt-10b, Wnt-4 and Wnt-7a mRNA were increased by about 3.1-fold, 2.2-fold and 1.4-fold independently after transplantation. Furthermore, the expressions of β-catenin and β-catenin target genes (cyclin D1 and c-myc) were elevated by about 3-fold, 1.5-fold and 2-fold respectively in the grafted epidermal sheets (P < 0.01). Conclusion Traumatic microenvironment can induce epidermal cell dedifferentiation, when the Wnt/β -catenin signaling pathway may play an important role. Key words: Wounds and injuries; Epidermis; Dedifferentiation; Signal transduction; Wnt/β-catenin signaling pathway

Effects of Wnt-1 on the Growth and Apoptosis of FRTL-5 Cells

Background: Wnt proteins are major signaling molecules involved in embryonic induction, generation of cell polarity and the cell fate decision. A central player in the Wnt signaling pathways is beta-catenin. Several studies have suggested that the Wnt/beta-catenin signaling pathway may be involved in the physiologic/pathologic control of thyroid cell growth and function. Methods: We investigated the effect of thyroid-stimulating hormone (TSH) on the expression of Wnt proteins in FRTL-5 cells. To evaluate the effect of Wnt-1 on FRTL-5 cells growth, we isolated a stable cell line that overexpressed Wnt-1 (W1), and a vector-transfected cell clone (V3) was used as a control. We investigated the differences in the cellular growth rate, the cell cycle and cell apoptosis in the W1 and V3 cell lines. Results: TSH caused a significant increase in the Wnt-1 level and a pronounced decrease in both the active and total beta-catenin levels in the FRTL-5 cells. The growth rate, the percentage of cells in the S/G2/M phase and the c-myc level were significantly higher in the W1 cells compared with the V3 cells. There was no change in the beta-catenin level and the cyclin D1 level in the W1 cells compared with the V3 cells. The cellular apoptosis induced by actinomycin-D seemed to be significantly decreased because the level of bcl-2 was increased in the W1 cells compared with the V3 cells. Conclusion: The FRTL-5 cells expressed Wnt-1 protein, and TSH increased the Wnt-1 expression, and it paradoxically decreased beta-catenin in the FRTL-5 cells. Overexpression of Wnt-1 in the FRTL-5 cells increased cell growth and it decreased apoptosis. Growth stimulation by Wnt-1 overexpression was not mediated by beta-catenin (the canonical Wnt pathway), but seemed to be mediated by activation of the

A WNT4 Mutation Associated With Müllerian-Duct Regression and Virilization in a 46, XX Woman

A WNT4 Mutation Associated With Müllerian-Duct Regression and Virilization in a 46, XX Woman

Epithelial-mesenchymal transition in gastric cancer (Review).

Endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), surgical gastrectomy, and chemotherapy are therapeutic options of gastric cancer; how-ever, prognosis of advanced gastric cancer patients is still poor. Gastric cancer cells with fibroblastoid morphological changes show increased motility and invasiveness due to decreased cell-cell adhesion, which are reminiscent of epithelial-mesenchymal transition (EMT) during embryonic development. Here, EMT signaling networks in gastric cancer were reviewed. E-cadherin at adherens junction is a key molecular target of EMT. CDH1 gene at human chromosome 16q22.1 encodes E-cadherin. Familial diffuse type gastric cancer occurs due to germ-line mutations of the CDH1 gene. Down-regulation of E-cadherin function due to mutation, deletion, CpG hyper-methylation, and SNAIL (SNAI1)- or SIP1-mediated transcriptional repression of the CDH1 gene leads to EMT in gastric cancer. Amplification of ERBB2, MET, FGFR2, PIK3CA, AKT1 genes, up-regulation of WNT2, WNT2B, WNT8B, and down-regulation of SFRP1 lead to EMT in gastric cancer through GSK3beta inhibition and following SNAIL-mediated CDH1 repression. Claudin (CLDN) and PAR3/PAR6/aPKC complex at tight junction are other key molecular targets of EMT. CLDN23 gene is down-regulated in intestinal type gastric cancer. Down-regulation of PAR3/PAR6/aPKC complex also leads to EMT. Single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) of genes encoding EMT signaling molecules will be identified as novel risk factors of gastric cancer. In addition, antibodies, RNAi compounds, and small molecular inhibitors for EMT signaling molecules will be developed as novel therapeutic agents for gastric cancer. Personalized medicine based on the combination of genetic screening and novel therapeutic agents could dramatically improve the prognosis of gastric cancer patients in the future.