SIRT4对胃癌细胞增殖及周期的影响
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摘要
目的:探讨SIRT4对胃癌细胞增殖及细胞周期的作用及其机制。方法:用慢病毒构建过表达SIRT4的胃癌细胞株SGC-7901和MNK45,通过体外细胞增殖活力实验和平板克隆实验研究过表达SIRT4对胃癌细胞体外增殖活力和克隆形成能力的影响;进一步通过细胞周期实验研究SIRT4对胃癌细胞周期及相关周期蛋白的影响。结果:过表达SIRT4能显著抑制胃癌细胞SGC-7901和MNK45的体外增殖活力和克隆形成能力(P<0.05);过表达SIRT4通过下调p-ERK、cyclin D和cyclin E水平(P<0.05),导致细胞G1周期阻滞。结论:SIRT4在胃癌中可能起到抑癌基因的作用。
Objective: To investigate the effect and mechanism of SIRT4 on the proliferation and cell cycle of gastric cancer cells. Methods: We constructed SIRT4-overexpressed gastric cancer cell-lines SGC-7901 and MNK45 by lentiviral-mediated transduction. On studying cell viability and proliferation activity, we noted the effects of overexpressed SIRT4 on the proliferation and clone forming ability of gastric cancer cells in vitro. In addition, we studied the cell cycle in an attempt to gain insights into the cellular mechanism. Results: Overexpression of SIRT4 significantly inhibited the proliferation and clone forming ability of the gastric cancer cells SGC-7901 and MNK45 in vitro. Furthermore, overexpression of SIRT4 induced G1 cell cycle arrest via downregulation of p-ERK, cyclin D, and cyclin E. Conclusion: SIRT4 may play a role as a tumor suppressor gene in gastric cancer.
Objective: To investigate the effect and mechanism of SIRT4 on the proliferation and cell cycle of gastric cancer cells. Methods: We constructed SIRT4-overexpressed gastric cancer cell-lines SGC-7901 and MNK45 by lentiviral-mediated transduction. On studying cell viability and proliferation activity, we noted the effects of overexpressed SIRT4 on the proliferation and clone forming ability of gastric cancer cells in vitro. In addition, we studied the cell cycle in an attempt to gain insights into the cellular mechanism. Results: Overexpression of SIRT4 significantly inhibited the proliferation and clone forming ability of the gastric cancer cells SGC-7901 and MNK45 in vitro. Furthermore, overexpression of SIRT4 induced G1 cell cycle arrest via downregulation of p-ERK, cyclin D, and cyclin E. Conclusion: SIRT4 may play a role as a tumor suppressor gene in gastric cancer.
引文
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[3]HAIGIS M C,MOSTOSLAVSKY R,HAIGIS K M,et al.SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells[J].Cell,2006,126(5):941-954.
[4]JEONG S M,XIAO C,FINLEY L W,et al.SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism[J].Cancer Cell,2013,23(4):450-463.
[5]CSIBI A,FENDT S M,LI C,et al.The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4[J].Cell,2013,153(4):840-854.
[6]MIYO M,YAMAMOTO H,KONNO M,et al.Tumour-suppressive function of SIRT4 in human colorectal cancer[J].Br J Cancer,2015,113(3):492-499.
[7]NAKAHARA Y,YAMASAKI M,SAWADA G,et al.Downregulation of SIRT4 expression is associated with poor prognosis in esophageal squamous cell carcinoma[J].Oncology,2016,90(6):347-355.
[8]HUANG G,CHENG J,YU F,et al.Clinical and therapeutic significance of sirtuin-4 expression in colorectal cancer[J].Oncol Rep,2016,35(5):2801-2810.
[9]HUANG G,CUI F,YU F,et al.Sirtuin-4(SIRT4)is downregulated and associated with some clinicopathological features in gastric adenocarcinoma[J].Biomed Pharmacother,2015,72:135-139.
[10]ROTH M CHEN W Y.Sorting out functions of sirtuins in cancer[J].Oncogene,2013,21(36):354-359.
[11]CHA E J,NOH S J,KWON K S,et al.Expression of DBC1and SIRT1 is associated with poor prognosis of gastric carci-noma[J].Clin Cancer Res,2009,15(13):4453-4459.
[12]STUNKEL W,PEH B K,TAN Y C,et al.Function of the SIRT1 protein deacetylase in cancer[J].Biotechnol J,2007,2(11):1360-1368.
[13]HUFFMAN D M,GRIZZLE W E,BAMMAN M M,et al.SIRT1 is significantly elevated in mouse and human prostate cancer[J].Cancer Res,2007,67(14):6612-6618.
[14]HIDA Y,KUBO Y,MURAO K,et al.Strong expression of a longevity-related protein,SIRT1,in Bowen’s disease[J].Arch Dermatol Res,2007,299(2):103-106.
[15]WANG R H,SENGUPTA K,LI C,et al.Impaired DNAdamage response,genome instability,and tumorigenesis in SIRT1 mutant mice[J].Cancer Cell,2008,14(4):312-323.
[16]FIRESTEIN R,BLANDER G,MICHAN S,et al.The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth[J].PLoS One,2008,3(4):e2020.
[17]JEONG S M,LEE A,LEE J,et al.SIRT4 suppresses tumor formation in genetic models of Myc-induced B cell lymphoma[J].J Biol Chem,2013,16(3):275-281.
[18]HALL M,PETERS G.Genetic alterations of cyclins,cyclindependent kinases,and Cdk inhibitors in human cancer[J].Adv Cancer Res,1996,68:67-108.
[19]CHAMBARD J C,LEFLOCH R,POUYSSEGUR J,et al.ERK implication in cell cycle regulation[J].Biochim Biophys Acta,2007,1773(8):1299-310.
[20]OHTSUBO M,THEODORAS A M,SCHUMACHER J,et al.Human cyclin E,a nuclear protein essential for the G1-to-S phase transition[J].Mol Cell Biol,1995,15(5):2612-2624.
[21]OHTSUBO M,ROBERTS J M.Cyclin-dependent regulation of G1 in mammalian fibroblasts[J].Science,1993,259(5103):1908-1912.