Department of Pathology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea.
Biochem Biophys Res Commun. 2013 Nov 1;440(4):689-95. doi: 10.1016/j.bbrc.2013.09.123. Epub 2013 Oct 5.
Gastrokine 1 (GKN1) protects the gastric antral mucosa and promotes healing by facilitating restitution and proliferation after injury. GKN1 is down-regulated in Helicobacter pylori-infected gastric epithelial cells and loss of GKN1 expression is tightly associated with gastric carcinogenesis. However, the underlying mechanisms as a tumor suppressor are largely unknown. Presently, the hydrophobic region and BRICHOS domain of GKN1, pGKN1(D13N), pGKN1(Δ68-199), and pGKN1(Δ1-67,165-199) were shown to suppress gastric cancer cell growth and recapitulate GKN1 functions. As well, the hydrophobic region and BRICHOS domain of GKN1 had a synergistic anti-cancer effect with 5-FU on tumor cell growth, implying that the NH2-terminal hydrophobic region and BRICHOS domain of GKN1 are sufficient for tumor suppression, thereby suggesting a therapeutic intervention for gastric cancer. Also, its domain inducing endogenous miR-185 directly targeted the epigenetic effectors DNMT1 and EZH2 in gastric cancer cells. Our results suggest that the NH2-terminal hydrophobic region and BRICHOS domain of GKN1 are sufficient for its tumor suppressor activities.
胃泌素 1（GKN1）通过促进损伤后的修复和增殖来保护胃窦黏膜并促进愈合。在幽门螺杆菌感染的胃上皮细胞中，GKN1 下调，GKN1 表达的丧失与胃癌的发生密切相关。然而，作为肿瘤抑制因子的潜在机制在很大程度上尚不清楚。目前，GKN1 的疏水区和 BRICHOS 结构域、pGKN1(D13N)、pGKN1(Δ68-199) 和 pGKN1(Δ1-67,165-199) 被证明可抑制胃癌细胞生长并重现 GKN1 的功能。此外，GKN1 的疏水区和 BRICHOS 结构域与 5-FU 对肿瘤细胞生长具有协同的抗癌作用，这表明 GKN1 的 NH2-末端疏水区和 BRICHOS 结构域足以抑制肿瘤，从而为胃癌提供了一种治疗干预手段。此外，其诱导内源性 miR-185 的结构域可直接靶向胃癌细胞中的表观遗传效应因子 DNMT1 和 EZH2。我们的研究结果表明，GKN1 的 NH2-末端疏水区和 BRICHOS 结构域足以发挥其肿瘤抑制活性。
