结直肠癌中ATBF1基因功能分析
|
摘要
目的对ATBF1基因在结直肠癌中功能进行研究。方法通过免疫组织化学研究146例结直肠癌患者的癌组织及癌旁组织和激光共聚焦研究常见结直肠癌细胞株中ATBF1表达情况,免疫印迹检测ATBF1-A蛋白在高、中、低分化的癌组织及癌旁组织和常见细胞株中的表达,RT-PCR检测38例中分化结直肠癌组织及癌旁组织和常见细胞株中ATBF1m RNA的表达情况。结果ATBF1在结直肠癌癌旁组织中的表达量高于癌组织,分化程度越高表达量越高,与转移呈负相关,但与ATBF1m RNA的表达无明显相关性。在不同细胞株中ATBF1蛋白及ATBF1m RNA表达量不同。结论 ATBF1在结直肠癌中呈现抑癌基因作用,与肿瘤分化程度及淋巴转移程度相关。
Objective To investigate the function of AT motif binding factor 1(ATBF1) in colorectal cancer.Methods ATBF1 protein expression was detected in 146 pairs of colorectal cancer tissues and the adjacent tissues using immunohistochemistry.ATBF1 protein expression was also examined in colorectal cell lines with laser confocal microscopy.ATBF1-A protein expression in colorectal cancer tissues of different differentiation grades and in the colorectal cancer cell lines were detected with Western blotting.The expressions of ATBF1 m RNA in 38 moderately differentiated colorectal cancer tissues and the paired adjacent tissues and in the colorectal cancer cell lines were tested using RT-PCR.Results ATBF1 protein expression levels in colorectal cancer tissues and adjacent tissues differed significantly(P<0.001),and its expression increased significantly in positive correlation with the grade of tumor differentiation(P<0.001) but in negative correlation with tumor metastasis.ATBF1 m RNA expression and ATBF1 protein expression were significantly correlated(P=0.100).The ATBF1 protein and m RNA expressions also differed significantly among different colorectal cancer cell lines.Conclusion ATBF1 executes the role of a tumor suppressor gene in colorectal cancer,and its protein expression is associated with tumor differentiation and lymph node metastases.
Objective To investigate the function of AT motif binding factor 1(ATBF1) in colorectal cancer.Methods ATBF1 protein expression was detected in 146 pairs of colorectal cancer tissues and the adjacent tissues using immunohistochemistry.ATBF1 protein expression was also examined in colorectal cell lines with laser confocal microscopy.ATBF1-A protein expression in colorectal cancer tissues of different differentiation grades and in the colorectal cancer cell lines were detected with Western blotting.The expressions of ATBF1 m RNA in 38 moderately differentiated colorectal cancer tissues and the paired adjacent tissues and in the colorectal cancer cell lines were tested using RT-PCR.Results ATBF1 protein expression levels in colorectal cancer tissues and adjacent tissues differed significantly(P<0.001),and its expression increased significantly in positive correlation with the grade of tumor differentiation(P<0.001) but in negative correlation with tumor metastasis.ATBF1 m RNA expression and ATBF1 protein expression were significantly correlated(P=0.100).The ATBF1 protein and m RNA expressions also differed significantly among different colorectal cancer cell lines.Conclusion ATBF1 executes the role of a tumor suppressor gene in colorectal cancer,and its protein expression is associated with tumor differentiation and lymph node metastases.
引文
[1]中华人民共和国卫生和计划生育委员会医政医管局,中华医学会肿瘤学分会.中国结直肠癌诊疗规范(2015版)[J].中华消化外科杂志,2015,14(10):783-99.
[2]Miura Y,Tam T,Ido A,et al.Cloning and characterization of an ATBF1 isoform that expresses in a neuronal differentiationdependent manner[J].J Biol Chem,1995,270(45):26840-8.
[3]Sun X,Frierson HF,Chen C,et al.Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer[J].Nat Genet,2005,37(4):407-12.
[4]Sun X,Li J,Dong FN,et al.Characterization of nuclear localization and SUMOylation of the ATBF1 transcription factor in epithelial cells[J].PLo S One,2014,9(3):e92746.
[5]Li M,Fu X,Ma G,et al.Atbf1 regulates pubertal mammary gland development likely by inhibiting the pro-proliferative function of estrogen-ER signaling[J].PLo S One,2012,7(12):e51283.
[6]Jung CG,Uhm KO,Miura Y,et al.Beta-amyloid increases the expression level of ATBF1 responsible for death in cultured cortical neurons[J].Mol Neurodegener,2011,6:47.
[7]Kim TS,Kawaguchi M,Suzuki M,et al.The ZFHX3(ATBF1)transcription factor induces PDGFRB,which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress[J].Dis Model Mech,2010,3(11/12):752-62.
[8]Helenius IT,Haake RJ,Kwon YJ,et al.Identification of drosophila Zfh2 as a mediator of hypercapnic immune regulation by a GenomeWide RNA interference screen[J].J Immunol,2016,196(2):655-67.
[9]Nojiri S,Joh T,Miura Y,et al.ATBF1 enhances the suppression of STAT3 signaling by interaction with PIAS3[J].Biochem Biophys Res Commun,2004,314(1):97-103.
[10]Grasso CS,Wu YM,Robinson DR,et al.The mutational landscape of lethal castration-resistant prostate cancer[J].Nature,2012,487(746):239-43.
[11]Sun X,Li J,Sica G,et al.Interruption of nuclear localization of ATBF1 during the histopathologic progression of head and neck squamous cell carcinoma[J].Head Neck,2013,35(7):1007-14.
[12]Mabuchi M,Kataoka H,Miura Y,et al.Tumor suppressor,AT motif binding factor 1(ATBF1),translocates to the nucleus with runt domain transcription factor 3(RUNX3)in response to TGF-beta signal transduction[J].Biochem Biophys Res Commun,2010,398(2):321-5.
[13]An CH,Kim SS,Kang MR,et al.Frameshift mutations of ATBF1,WNT9A,CYLD and PARK2 in gastric and colorectal carcinomas with high microsatellite instability[J].Pathology,2010,42(6):583-5.
[14]Dong XY,Sun X,Guo P,et al.ATBF1 inhibits estrogen receptor(ER)function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells[J].J Biol Chem,2010,285(43):32801-9.
[15]Kaspar P,DvorákováM,KrálováJ,et al.Myb-interacting protein,ATBF1,represses transcriptional activity of Myb oncoprotein[J].J Biol Chem,1999,274(20):14422-8.
[16]Sun X,Xing C,Fu X,et al.Additive effect of Zfhx3/Atbf1 and Pten deletion on mouse prostatic tumorigenesis[J].J Genetics Genomics,2015,42(7):373-82.
[17]Sakata N,Kaneko S,Ikeno S,et al.TGF-βsignaling cooperates with AT Motif-Binding factor-1 for repression of theα-Fetoprotein promoter[J].J Signal Transduct,2014:970346.
[18]Li M,Zhao D,Ma G,et al.Upregulation of ATBF1 by progesteronePR signaling and its functional implication in mammary epithelial cells[J].Biochem Biophys Res Commun,2013,430(1):358-63.
[19]Zhang Z,Yamashita H,Toyama T,et al.ATBF1-a messenger RNA expression is correlated with better prognosis in breast cancer[J].Clin Cancer Res,2005,11(1):193-8.
[20]Mori Y,Kataoka H,Miura Y,et al.Subcellular localization of ATBF1 regulates MUC5AC transcription in gastric cancer[J].Int J Cancer,2007,121(2):241-7.
[2]Miura Y,Tam T,Ido A,et al.Cloning and characterization of an ATBF1 isoform that expresses in a neuronal differentiationdependent manner[J].J Biol Chem,1995,270(45):26840-8.
[3]Sun X,Frierson HF,Chen C,et al.Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer[J].Nat Genet,2005,37(4):407-12.
[4]Sun X,Li J,Dong FN,et al.Characterization of nuclear localization and SUMOylation of the ATBF1 transcription factor in epithelial cells[J].PLo S One,2014,9(3):e92746.
[5]Li M,Fu X,Ma G,et al.Atbf1 regulates pubertal mammary gland development likely by inhibiting the pro-proliferative function of estrogen-ER signaling[J].PLo S One,2012,7(12):e51283.
[6]Jung CG,Uhm KO,Miura Y,et al.Beta-amyloid increases the expression level of ATBF1 responsible for death in cultured cortical neurons[J].Mol Neurodegener,2011,6:47.
[7]Kim TS,Kawaguchi M,Suzuki M,et al.The ZFHX3(ATBF1)transcription factor induces PDGFRB,which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress[J].Dis Model Mech,2010,3(11/12):752-62.
[8]Helenius IT,Haake RJ,Kwon YJ,et al.Identification of drosophila Zfh2 as a mediator of hypercapnic immune regulation by a GenomeWide RNA interference screen[J].J Immunol,2016,196(2):655-67.
[9]Nojiri S,Joh T,Miura Y,et al.ATBF1 enhances the suppression of STAT3 signaling by interaction with PIAS3[J].Biochem Biophys Res Commun,2004,314(1):97-103.
[10]Grasso CS,Wu YM,Robinson DR,et al.The mutational landscape of lethal castration-resistant prostate cancer[J].Nature,2012,487(746):239-43.
[11]Sun X,Li J,Sica G,et al.Interruption of nuclear localization of ATBF1 during the histopathologic progression of head and neck squamous cell carcinoma[J].Head Neck,2013,35(7):1007-14.
[12]Mabuchi M,Kataoka H,Miura Y,et al.Tumor suppressor,AT motif binding factor 1(ATBF1),translocates to the nucleus with runt domain transcription factor 3(RUNX3)in response to TGF-beta signal transduction[J].Biochem Biophys Res Commun,2010,398(2):321-5.
[13]An CH,Kim SS,Kang MR,et al.Frameshift mutations of ATBF1,WNT9A,CYLD and PARK2 in gastric and colorectal carcinomas with high microsatellite instability[J].Pathology,2010,42(6):583-5.
[14]Dong XY,Sun X,Guo P,et al.ATBF1 inhibits estrogen receptor(ER)function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells[J].J Biol Chem,2010,285(43):32801-9.
[15]Kaspar P,DvorákováM,KrálováJ,et al.Myb-interacting protein,ATBF1,represses transcriptional activity of Myb oncoprotein[J].J Biol Chem,1999,274(20):14422-8.
[16]Sun X,Xing C,Fu X,et al.Additive effect of Zfhx3/Atbf1 and Pten deletion on mouse prostatic tumorigenesis[J].J Genetics Genomics,2015,42(7):373-82.
[17]Sakata N,Kaneko S,Ikeno S,et al.TGF-βsignaling cooperates with AT Motif-Binding factor-1 for repression of theα-Fetoprotein promoter[J].J Signal Transduct,2014:970346.
[18]Li M,Zhao D,Ma G,et al.Upregulation of ATBF1 by progesteronePR signaling and its functional implication in mammary epithelial cells[J].Biochem Biophys Res Commun,2013,430(1):358-63.
[19]Zhang Z,Yamashita H,Toyama T,et al.ATBF1-a messenger RNA expression is correlated with better prognosis in breast cancer[J].Clin Cancer Res,2005,11(1):193-8.
[20]Mori Y,Kataoka H,Miura Y,et al.Subcellular localization of ATBF1 regulates MUC5AC transcription in gastric cancer[J].Int J Cancer,2007,121(2):241-7.