J Gastric Cancer.  2014 Sep;14(3):147-155. 10.5230/jgc.2014.14.3.147.

The Role of Gastrokine 1 in Gastric Cancer

• Yoon JH
• Choi WS
• Kim O
• Park WS

• KMID: 2372525
• DOI: http://doi.org/10.5230/jgc.2014.14.3.147

Abstract

Homeostatic imbalance between cell proliferation and death in gastric mucosal epithelia may lead to gastritis and gastric cancer. Despite abundant gastrokine 1 (GKN1) expression in the normal stomach, the loss of GKN1 expression is frequently detected in gastric mucosa infected with Helicobacter pylori, as well as in intestinal metaplasia and gastric cancer tissues, suggesting that GKN1 plays an important role in gastric mucosal defense, and the gene functions as a gastric tumor suppressor. In the stomach, GKN1 is involved in gastric mucosal inflammation by regulating cytokine production, the nuclear factor-kappaB signaling pathway, and cyclooxygenase-2 expression. GKN1 also inhibits the carcinogenic potential of H. pylori protein CagA by binding to it, and up-regulates antioxidant enzymes. In addition, GKN1 reduces cell viability, proliferation, and colony formation by inhibiting cell cycle progression and epigenetic modification by down-regulating the expression levels of DNMT1 and EZH2, and DNMT1 activity, and inducing apoptosis through the death receptor-dependent pathway. Furthermore, GKN1 also inhibits gastric cancer cell invasion and metastasis via coordinated regulation of epithelial mesenchymal transition-related protein expression, reactive oxygen species production, and PI3K/Akt signaling pathway activation. Although the modes of action of GKN1 have not been clearly described, recent limited evidence suggests that GKN1 acts as a gastric-specific tumor suppressor. This review aims to discuss, comment, and summarize the recent progress in the understanding of the role of GKN1 in gastric cancer development and progression.

Keyword

GKN1 protein; Homeostasis; Gastritis; Stomach neoplasms; Tumor suppressor gene

MeSH Terms

Apoptosis
Cell Cycle
Cell Proliferation
Cell Survival
Cyclooxygenase 2
Epigenomics
Gastric Mucosa
Gastritis
Genes, Tumor Suppressor
Helicobacter pylori
Homeostasis
Inflammation
Metaplasia
Neoplasm Metastasis
Reactive Oxygen Species
Stomach
Stomach Neoplasms*
Cyclooxygenase 2
Reactive Oxygen Species

Figure

• 

  Fig. 1 Role of GKN1 in gastric cancer. GKN1 induces apoptosis through the death receptor dependent pathway and inhibits Helicobacter pylori CagA injection into gastric epithelial cells. GKN1 also reduces reactive oxygen species production by up-regulating the expression of antioxidant enzymes, such as MnSOD and catalase. At the intracellular level of gastric epithelial cells, GKN1 induces miR-185 expression by down-regulating c-myc, which in turn inhibits epigenetic modification of genomic DNA and stimulates the expression of negative cell cycle regulators, including p53, p21, and p16. In addition, GKN1 inhibits epithelial mesenchymal transition by inactivating PI3K/Akt and β-catenin signaling pathway, resulting in the disruption of invasion and metastasis of gastric cancer cells. Blue line: stimulator, Red line: inhibitor. GKN1 = gastrokine 1; ROS = reactive oxygen species; NF-κB = nuclear factor-κB; COX2 = cyclooxygenase-2; CASP3 = caspase 3; CASP8 = caspase 8; CDH1 = cadherin 1; DNMT1 = DNA methyltransferase 1; EZH2 = enhancer of zeste homolog 2; PI3K = phosphatidylinositol 3-kinase; IKKα/β = IκB kinase α/β.

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