Gastrokine 1 induces senescence and apoptosis through regulating telomere length in gastric cancer
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Jung Hwan Yoon1, Ho Seok Seo2, Won Seok Choi1, Olga Kim1, Suk Woo Nam1,3, Jung Young Lee1,3, Won Sang Park1,3
1Department of Pathology, College of Medicine, The Catholic University of Korea, Banpo-dong, Seocho-gu, Seoul 137-701, South Korea
2Department of General Surgery, College of Medicine, The Catholic University of Korea, Banpo-dong, Seocho-gu, Seoul 137-701, South Korea
3Functional RNomics Research Center, College of Medicine, The Catholic University of Korea, Banpo-dong, Seocho-gu, Seoul 137-701, South Korea
Won Sang Park, e-mail: firstname.lastname@example.org
Keywords: GKN1, telomeres, telomerase, senescence, apoptosis
Received: July 29, 2014 Accepted: October 10, 2014 Published: December 10, 2014
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.
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