Abstract
The present study aims to investigate whether gastrokine 1 (GKN1) induces senescence and apoptosis in gastric cancer cells by regulating telomere length and telomerase activity. Telomere length, telomerase activity, and hTERT expression decreased significantly in AGSGKN1 and MKN1GKN1 cells. Both stable cell lines showed increased expression of TRF1 and reduced expression of the hTERT and c-myc proteins. In addition, TRF1 induced a considerable decrease in cell growth, telomerase activity, and expression of hTERT mRNA and protein. GKN1 completely counteracted the effects of c-myc on cell growth, telomere length, and telomerase activity. Interestingly, GKN1 directly bound to c-myc and down-regulated its expression as well as inhibited its binding to the TRF1 protein and a hTERT promoter. Furthermore, GKN1 triggered senescence, followed by apoptosis via up-regulating the p53, p21, p27, and p16 proteins and down-regulating Skp2. Telomere length in 35 gastric cancers was shortened significantly compared with the corresponding gastric mucosae, whereas GKN1 expression was inversely correlated with telomere length and c-myc and hTERT mRNA expression. Taken together, these results suggest that GKN1 may shorten telomeres by acting as a potential c-myc inhibitor that eventually leads to senescence and apoptosis in gastric cancer cells.
Highlights
Telomeres, which consist of a repetitive G-rich DNA sequence and telomeric protein, play an important role in the prevention of end-to-end chromosome fusion and genomic instability [1, 2, 3]
We tested telomere length in AGS and MKN1 cells after transient transfection with mock or gastrokine 1 (GKN1) to investigate whether the inhibition of cell growth by GKN1 is associated with the telomere attrition
Telomeres play an important role in the maintenance of genomic stability and aberrant deregulation of telomeres has been well documented in gastric cancer [17]
Summary
Telomeres, which consist of a repetitive G-rich DNA sequence and telomeric protein, play an important role in the prevention of end-to-end chromosome fusion and genomic instability [1, 2, 3]. Telomere length in healthy cells is highly regulated in a tissue- and cell type-specific manner and is dependent on mitotic turnover rate, telomerase activity, and telomerase-associated factors [5]. Several studies, including those in humans, have observed shortening of telomeres in vivo during aging [6]. Defects in telomere maintenance contribute to the initiation of genomic instability during carcinogenesis, including gastric cancer [8, 9]. Little is known about telomere maintenance in gastric mucosal epithelial cells and its contribution to gastric carcinogenesis
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