Inactivation of the <i>Gastrokine 1</i> gene in gastric adenomas and carcinomas

Yoon, Jung Hwan; Song, Jae Yen; Cao, Zhiyun; Jin, Meishan; Kang, Young Hwi; Nam, Suk Woo; Lee, Jung Young; Park, Won Sang

doi:10.1002/path.2838

Cited by 53 publications

(103 citation statements)

References 16 publications

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“…In contrast, no somatic mutation of RhoA was detected in this study, suggesting that somatic mutations may not be a cause of RhoA activation in these gastric cancers (data not shown). As the gastric specific tumor suppressor GKN1 was frequently downregulated in gastric cancers [19], we analyzed GKN1 inactivation as a possible cause of RhoA overexpression. In our analysis of RhoA and GKN1 expression in gastric cancers, GKN1 mRNA expression was inversely correlated with RhoA expression (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The primer sequences are described in Table 1. Each polymerase chain reaction (PCR) procedure was performed under standard conditions, as previously described [19]. The reaction mixture was denatured at 94°C for 12 min and then incubated for 35 cycles (denaturing at 94°C for 40 s, annealing at 50-54°C for 40 s, and extension at 72°C for 40 s).…”

Section: Mutational Analysismentioning

confidence: 99%

“…For quantitative PCR (qRCR), 50 ng cDNA was amplified with Fullvelocity SYBR Green qPCR master mix (Stratagene, La Jolla, CA, USA) and each of the forward and reverse primers at 20 pmol/ll with use of a Stratagene Mx 3000P qPCR system with techniques previously described [19]. The specific oligonucleotide primers for mRNA were synthesized according to published information on the GKN1 gene, as described in Table 1.…”

Section: Messenger Rna Expression Of Gkn1 and Rhoamentioning

confidence: 99%

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Gastrokine 1 inhibits gastric cancer cell migration and invasion by downregulating RhoA expression

et al. 2016

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Background We investigated whether GKN1, a gastric tumor suppressor, contributes to the progression of gastric cancer by regulating RhoA expression. Methods We analyzed the expression of GKN1, RhoA, miR-185, and miR-34a in 35 gastric cancer tissues, and compared their expression with T category and TNM stage. Cell migration and invasion, as well as the expression of epithelial-to-mesenchymal transition (EMT)-related proteins, were assessed in GKN1-and RhoA small interfering RNA (siRhoA)-transfected and recombinant-GKN1-treated AGS and MKN1 gastric cancer cells. Results Expression of RhoA protein and messenger RNA (mRNA) was increased in 15 (42.9 %) and 17 (48.6 %) of 35 gastric cancer tissues respectively, and was associated with higher T category and TNM stage. GKN1 expression was significantly decreased in 27 gastric cancers (77.1 %) with a higher T category, and was inversely correlated with RhoA mRNA expression. In AGS and MKN1 cells, GKN1 expression increased miR-185 and miR-34a expression and reduced RhoA mRNA and protein expression. A positive relationship between GKN1 and miR-34a and miR-185 expression and an inverse relationship between miR-34a and RhoA expression were observed in gastric cancer tissues. Cell migration and invasiveness were markedly decreased in GKN1-and siRhoA-transfected cells. GKN1 expression and silencing of RhoA decreased the expression of the proteins Snail, Slug, and vimentin. Furthermore, miR-185 and miR-34a silencing in MKN1 cells transfected with GKN1 stimulated cell migration and invasion, and increased the expression of EMT-related proteins. Conclusion Our data suggest that GKN1 may inhibit gastric cancer cell migration and invasion by downregulating RhoA expression in a miR-185-and miR-34a-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Section: Mutational Analysismentioning

confidence: 99%

Section: Messenger Rna Expression Of Gkn1 and Rhoamentioning

confidence: 99%

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Gastrokine 1 inhibits gastric cancer cell migration and invasion by downregulating RhoA expression

et al. 2016

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“…As GKN1 is a novel autocrine/paracrine protein specifically expressed in gastric mucosa and functions as a gastric specific tumor suppressor, 20,50 we set out to determine whether NKX6.3 activity in gastric differentiation is dependent on GKN1. …”

Section: Discussionmentioning

confidence: 99%

“…20 Immunohistochemistry and immunofluorescent analysis were processed according to standard procedures as described in the Supplementary Methods.…”

Section: Immunohistochemistry and Immunofluorescence Assaymentioning

confidence: 99%

Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

et al. 2016

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Intestinal metaplasia in gastric mucosa is considered a preneoplastic lesion that progresses to gastric cancer. However, the molecular networks underlying this lesion formation are largely unknown. NKX6.3 is known to be an important regulator in gastric mucosal epithelial differentiation. In this study, we characterized the effects of NKX6.3 that may contribute to gastric intestinal metaplasia. NKX6.3 expression was significantly reduced in gastric mucosae with intestinal metaplasia. The mRNA expression levels of both NKX6.3 and CDX2 predicted the intestinal metaplasia risk, with an area under the receiver operating characteristic curve value of 0.9414 and 0.9971, respectively. Notably, the NKX6.3 expression level was positively and inversely correlated with SOX2 and CDX2, respectively. In stable AGS NKX6.3 and MKN1 NKX6.3 cells, NKX6.3 regulated the expression of CDX2 and SOX2 by directly binding to the promoter regions of both genes. Nuclear NKX6.3 expression was detected only in gastric epithelial cells without intestinal metaplasia. Furthermore, NKX6.3-induced TWSG1 bound to BMP4 and inhibited BMP4-binding activity to BMPR-II. These data suggest that NKX6.3 might function as a master regulator of gastric differentiation by affecting SOX2 and CDX2 expression and the NKX6. Gastric cancer is still one of the malignancies with high incidence and mortality rates worldwide. 1 The stages of the precancerous cascade for gastric adenocarcinoma are a series of histologically recognizable changes in the gastric mucosa that follow a specific sequence: non-atrophic gastritis, multifocal atrophic gastritis, intestinal metaplasia, and dysplasia. 2-4 Of these, intestinal metaplasia is the replacement of gastric epithelium by epithelium displaying an intestinal phenotype with the appearance of goblet, Paneth, and absorptive cells. It is well known that Helicobacter pylori infection, high salt intake, smoking, and alcohol consumption are risk factors for gastric intestinal metaplasia. [5][6][7][8] Interestingly, altered expression of Muc5ac with the aberrant expression of Muc2 and caudal-related homologue 2 (CDX2) was detected in intestinal metaplasia of the stomach, which is characterized by the appearance of goblet cells and is considered to be a preneoplastic stage of gastric carcinogenesis. [9][10][11][12] Patients with gastric intestinal metaplasia showed a six-fold increased risk of gastric cancer than did those without gastric intestinal metaplasia. 13 Although much is known about the morphology and physiology of gastric intestinal metaplasia, the regulatory mechanisms that govern their intestinal differentiation still remain unclear.It was recently reported that NKX6.3, a third member of the NKX6 subfamily of NKX genes, is a novel transcription factor required for gastric epithelial differentiation. 14 In mouse embryos, NKX6.3 expression is restricted to endoderm-derived cells in the gastric antrum, pylorus, and proximal duodenum. 15 As a stratified squamous epithelium extends from the esophagus to the fundus of the m...

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The diagnostic value of serum gastrokine 1 (GKN1) protein in gastric cancer

et al. 2019

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Early detection of cancer provides effective treatment and saves lives. The objective of this study was to determine whether serum gastrokine 1 (GKN1) protein is a gastric cancer‐specific diagnostic biomarker. The serum concentration of GKN1 in healthy individuals (median: 6.34 ng/μL, interquartile range (IQR): 5.66‐7.54 ng/μL) was significantly higher compared with the levels in gastric cancer patients (median: 3.48 ng/μL, IQR: 2.90‐4.11 ng/μL; P < .0001). At the optimum cutoff (4.94 ng/μL) of serum GKN1 protein, the sensitivity and specificity were 91.2% and 96.0%, respectively, for gastric cancer. Using serum GKN1 protein as the diagnostic reference, the ROC curve showed a satisfactory diagnostic efficacy with an AUC value of 0.9954 (95% CI 0.9919‐0.9988) and Youden index of 0.8740. In addition, the diagnostic accuracy of the serum GKN1 protein at the optimum cutoff was 0.9675. Interestingly, serum GKN1 concentrations in patients with advanced gastric cancer (AGC; median: 3.11 ng/μL, IQR: 2.72‐3.72 ng/μL) were lower than in patients with early gastric cancer (EGC; median: 4.31 ng/μL, IQR: 3.88‐4.88 ng/μL). The diagnostic accuracies at the optimum serum GKN1 cutoff were 0.8912 and 0.9589 for EGC and AGC, respectively. Furthermore, the serum GKN1 concentrations robustly discriminated the patients with gastric cancer from the patients with colorectal, liver, lung, breast, pancreatic, ovary, and prostatic cancers with AUC values greater than 0.94. These data suggest that serum GKN1 is a promising and highly specific diagnostic biomarker for the prompt detection of early and advanced gastric cancers.

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Inactivation of the Gastrokine 1 gene in gastric adenomas and carcinomas

Cited by 53 publications

References 16 publications

Gastrokine 1 inhibits gastric cancer cell migration and invasion by downregulating RhoA expression

Gastrokine 1 inhibits gastric cancer cell migration and invasion by downregulating RhoA expression

Inactivation of NKX6.3 in the stomach leads to abnormal expression of CDX2 and SOX2 required for gastric-to-intestinal transdifferentiation

The diagnostic value of serum gastrokine 1 (GKN1) protein in gastric cancer

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