nm23-H1基因对肺癌细胞Wnt信号通路调控机制的实验研究
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摘要
肺癌的侵袭和转移是肺癌的恶性标志和特征,也是导致肺癌患者治疗失败和死亡的主要原因。肺癌的侵袭和转移是一个多因素作用、多基因参与、涉及细胞多个信号通路改变,并经过多个阶段才最终形成的复杂生物现象。因此,探讨肺癌侵袭转移相关细胞信号传导通路的变化,不仅有助于揭示肺癌侵袭转移的分子机制,而且将为阻断肺癌侵袭转移的信号传导和逆转肺癌侵袭转移表型提供新的靶点和途径。已经证明肿瘤转移抑制基因nm23-H1的低表达和杂合性缺失与肺癌的高转移性和预后不良有密切关系,并在调控“肺癌转移抑制级联”中发挥上游关键基因的作用。在nm23-H1基因缺失的人高转移大细胞肺癌细胞株L9981中转染野生型nm23-H1基因后,nm23-H1可通过调控“肺癌转移抑制级联”中多个转移相关基因的表达,逆转肺癌细胞的转移表型。Nm23-H1基因对“肺癌转移抑制级联”的调控作用可能是通过细胞中一些关键的信号传导通路来实现的。近年来的研究发现,Wnt信号通路的异常与肿瘤发生和侵袭转移有密切关系。为了探讨nm23-H1基因在“肺癌转移抑制级联”中对Wnt信号传导通路的调控作用及其分子机制,本研究在已经筛
Tumor metastasis is not only the malignant marker and characteristics of lung cancer, but also the main cause of failure to cure and lose their life of the patients with lung cancer. It is a complex biological behavior that dealed with many factors, genes, signal pathways and processes. Therefor, exploration of the changes of cell signal transduction related to invasion and metastasis in lung cancer will not only illuminate the molecular mechanism of tumor invasion and metastasis, but also provide a new targeting molecule and route for blocking signal transduction and reversing metastatic phenotype of lung cancer. Now, it has been proved that low expression and hetero-deletion of tumor metastasis suppressor gene nm23-Hl was closely correlated with the high metastasis ability and poor prognosis of patient with lung cancer. Nm23-Hl gene is a key and upstream regulative gene in the "lung cancer metastatic suppressive cascade". Transfection of wild type nm23-Hl cDNA into human high-metastatic large cell lung cancer cell, which has been proved that it had LOH of nm23-H1 gene, can regulate the
expression of metastatic relative genes and reverse the metastatic phenotypeof lung cancer cell lines. The molecular mechanism that nm23-Hl genesuppress lung cancer metastasis may be involved some important signalpathways. At present, it has been proved that the abnormality of Wnt signalpathway was closely correlated with the oncogenesis and development ofmalignant tumor. Up to now, however, we had not seen any reports on that ifnm23-Hl gene regulate "lung cancer metastatic suppressive cascade"simultaneously with Wnt signal pathway or not? How do the nm23-Hl generegulate the expression and activity of the key proteins and kinases in Wntsignal pathway? That if block of the activities of the key kinase in Wnt signalpathway can influnce the reversion effects of nm23-Hl gene for malignantbiological behavior and metastatic phenotype of lung cancer or not ? In orderto explore the regulation effects and mechanism of nm23-Hl gene in "lungcancer metastatic suppressive cascade" for Wnt signal transduction in lungcancer, based on our previous research results that human high-metastaticlarge cell lung cancer cell line L9981 had been screened and identified, thatthe L9981, L9981-pLXSN ( transfected with vector ) and L9981-nm23-Hl(transfected with nm23-Hl gene) lung cancer cell lines have beensuccessfully constructed, we carried out the following experimentalstudies:(l)The expression and kinase activity of GSK-30, P -catenin andphospho- ^ -catenin were detected in human high-metastatic large cell lungcancer cell lines L9981, L9981-pLXSN and L9981-nm23-Hl before and aftertransfection of nm23-Hl gene by Western blot, immunoprecipitation andisotope scintillative count; (2)The proliferative and invasive abilities of theL9981 lung cancer cell line were detected and compared by MTT and
Boyden chamber, before and after transfection of nm23-Hl gene; (3)The changes of expressive level and kinase activities of GSK-3P, P-catenin and phospho-P-catenin were determined in the L9981, L9981-pLXSN and L9981-nm23-Hl lung cancer cell lines before and after treating with GSK-3P kinase inhibitor, LiCL, by Western blot and immunoprecipitation and isotope scintillative count; (4)The effects of GSK-3P kinase inhibitor, LiCL , on the proliferative and invasive activities were detected in L9981, L9981-pLXSN and L9981-nm23-Hl lung cancer cell lines by MTT and Boyden chamber. The result in this study first showed in the world as follows:1.Western blot analysis showed that:(l) The expression of GSK-3P of cytoplasm and nucleus in L9981-nm23-Hl lung cancer cell line was remarkably higher than those in L9981 and L9981-pLXSN lung cancer cell lines (PO.001); (2)The expression of P -catenin of cytoplasm in L9981-nm23-Hl lung cancer cell line was significantly higher than those in L9981 and L9981-pLXSN lung cancer cell lines(P<0.01), but no significant difference of P -catenin expression of nucleus was found among the three lung cancer cell lines; (3)The expression of phospho- P -catenin of necleus in L9981-nm23-Hl cell line was remarkably higher than those in L9981 and L9981-pLXSN cell HnesCPO.OOl), but the expression of phospho- P -catenin of cytoplasm in L9981-nm23-Hl cell line was remarkably lower than those in L9981 and L9981-pLXSN cell lines(/><0.001).2.LiCL is a selective inhibitor of GSK-3P and activitor of Wnt signal pathway. The comparisons of time- and dose-dependent suppression of GSK-3P expression by LiCL showed that the most significant effection of LiCL on GSK-3P expression of cytoplasm and nucleus in the three lung
cancer cell lines was that the cell lines were treated with 20 mmol/L concentration for 60 min.3.After treatment of the three lung cancer cell lines with 20 mmol/L LiCL for 60 min, Western blot analysis showed that:(l) The GSK-3(3 expression of cytoplasm and nucleus in L9981-nm23-Hl lung cancer cell line was remarkably higher than those in L9981 and L9981-pLXSN cell lines (/><0.001);(2) The expression of P -catenin of cytoplasm in L9981-nm23-Hl lung cancer cell line was remarkably lower than those in L9981 and L9981-pLXSN cell lines(P<0.001), but the expression of 3 -catenin of nucleus in L9981-nm23-Hl cell line was significantly higher than those in L9981 and L9981-pLXSN cell lines(P<0.001);(3) The expression of phospho-3 -catenin of necleus in L9981-nm23-Hl cell line was remarkably higher than those in L9981 and L9981-pLXSN cell lines(P<0.001), however, the expression of phospho- P -catenin of cytoplasm in L9981-nm23-Hl cell line was remarkably lower than those in L9981 and L9981-pLXSN cell Iines(P<0.001).4. After treatment of the three cell lines with 20 mmol/L LiCL for 60 min, Western blot analysis showed that:(l)No significant difference of GSK-3p expression of cytoplasm and nucleus in L9981-nm23-Hl cell line was observed betwwen before and after treatment with 20mmol/L LiCL for 60min(P>0.05), but significant down-regulation of GSK-3P expression both in cytoplasm and nucleus was existed in L9981-pLXSN and L9981 cell lines after treatment with 20 mmol/L LiCL for 60 min(P<0.001); (2) P -catenin expression was remarkably increased in L9981-nm23-Hl nucleus and decreased in cytoplasm after treatment with 20mmol/L LiCL for
60min(/><0.001), but the ^ -catenin expression both of cytoplasm and nucleus was significantly upregulated in L9981 and L9981-pLXSN cell lines after treatment with 20 mmol/L for 60 min(.P<0.001); (3)The expression of phospho- P -catenin of cytoplasm and nucleus was downregulated in L9981-nm23-Hl , L9981-pLXSN and L9981 cell lines after treatment with 20mmol/L LiCL for 60min(P<0.001).5.GSK-3P activity assay were detected by immunoprecipitation and isotope scintillative count. GSK-3P activity of cytoplasm and nucleus in L9981-nm23-Hl cell line was remarkably higher than those in L9981 and L9981-pLXSN cell lines (PO.001), but no significant difference was observed between L9981-pLXSN and L9981 cell lines (P>0.05).6.The comparison of time- and dose-dependent suppression showed that: (l)The most significant effection of LiCL on GSK-3P activity in the three cell lines was observed when the cell lines were treated with 20 mmol/L LiCL for 60 min;(2) GSK-3P activity of cytoplasm and nucleus in L9981-nm23-Hl cell line was significantly higher than those in L9981-pLXSN and L9981 cell lines after treatment with 20 mmol/L LiCL for 60 min (P<0.00l), but no significant diffirence of GSK-3P activity of cytoplasm and nucleus was observed between L9981 and L9981-pLXSN cell lines (P>0.05); (3)The activities of GSK-3P both of cytoplasm and nucleus in L9981, L9981-pLXSN and L9981-nm23-Hl lung cancer cell lines after treatment with LiCL were remarkably lower than those before treatment with LiCL (PO.001).7.The cell proliferative and invasive abilities of L9981-nm23-Hl cell line were significantly lower than those in L9981 and L9981-pLXSN cell
lines (PO.001); The cell proliferative and invasive abilities of L9981-nm23-Hl, L9981, and L9981-pLXSN cell lines after treatment with 20 mmol/L LiCL were significantly higher than those before treatment with LiCL (PO.001); The cell proliferative and invasive abilities of L9981-nm23-Hl cell line was still significantly lower than those in L9981 and L9981-pLXSN cell lines after treatment with 20mmol/L LiCL(P<0.001).8.N0 significant difference of GSK-3P expression and activity, P -catenin and phospho- P -catenin expression of cytoplasm and nucleus was existed between L9981 and L9981-pLXSN lung cancer cell lines after treatment with LiCL (P>0.05). There was no significant difference of the proliferation and invasion in L9981 cell line after treatment with LiCL compared with L9981-pLXSN cell line (P>0.05).Conclusion:(l)Transfection of nm23-Hl gene can significantly upregulate the expression and activity of GSK-3p of cytoplasm and nucleus in the human high-metastasis large cell lung cancer cell line L9981; (2)nm23-Hl can significantly upregulate the expression of P -catenin of cytoplasm in the human high-metastasis large cell lung cancer cell line L9981, but not for P -catenin of nucleus; nm23-Hl can also significantly upregulate the expression of phospho-P -catenin of nucleus in L9981 lung cancer cell line; (3) LiCL can not only antagonize the effection of nm23-Hl gene on the upregulation effect for GSK-3p-. P -catenin and phospho- P -catenin in human high metastasis lung cancer cell line L9981, but also antagonize the reversion effects for cell proliferation and invasion of human high metastasis lung cancer cell line L9981. (4)The transduction of Wnt signal might be directly or indirectly suppressed through the upregulation of expression and
activity of GSK-3P in human high-metastasis large cell lung cancer cell lines by nm23-Hl gene. It may be one of the molecular mechanism that nm23-Hl gene regulate "lung cancer metastatic suppressive cascade" and reverse metastatic phenotype of human high-metastasis large cell lung cancer cell lines.
Tumor metastasis is not only the malignant marker and characteristics of lung cancer, but also the main cause of failure to cure and lose their life of the patients with lung cancer. It is a complex biological behavior that dealed with many factors, genes, signal pathways and processes. Therefor, exploration of the changes of cell signal transduction related to invasion and metastasis in lung cancer will not only illuminate the molecular mechanism of tumor invasion and metastasis, but also provide a new targeting molecule and route for blocking signal transduction and reversing metastatic phenotype of lung cancer. Now, it has been proved that low expression and hetero-deletion of tumor metastasis suppressor gene nm23-Hl was closely correlated with the high metastasis ability and poor prognosis of patient with lung cancer. Nm23-Hl gene is a key and upstream regulative gene in the "lung cancer metastatic suppressive cascade". Transfection of wild type nm23-Hl cDNA into human high-metastatic large cell lung cancer cell, which has been proved that it had LOH of nm23-H1 gene, can regulate the
expression of metastatic relative genes and reverse the metastatic phenotypeof lung cancer cell lines. The molecular mechanism that nm23-Hl genesuppress lung cancer metastasis may be involved some important signalpathways. At present, it has been proved that the abnormality of Wnt signalpathway was closely correlated with the oncogenesis and development ofmalignant tumor. Up to now, however, we had not seen any reports on that ifnm23-Hl gene regulate "lung cancer metastatic suppressive cascade"simultaneously with Wnt signal pathway or not? How do the nm23-Hl generegulate the expression and activity of the key proteins and kinases in Wntsignal pathway? That if block of the activities of the key kinase in Wnt signalpathway can influnce the reversion effects of nm23-Hl gene for malignantbiological behavior and metastatic phenotype of lung cancer or not ? In orderto explore the regulation effects and mechanism of nm23-Hl gene in "lungcancer metastatic suppressive cascade" for Wnt signal transduction in lungcancer, based on our previous research results that human high-metastaticlarge cell lung cancer cell line L9981 had been screened and identified, thatthe L9981, L9981-pLXSN ( transfected with vector ) and L9981-nm23-Hl(transfected with nm23-Hl gene) lung cancer cell lines have beensuccessfully constructed, we carried out the following experimentalstudies:(l)The expression and kinase activity of GSK-30, P -catenin andphospho- ^ -catenin were detected in human high-metastatic large cell lungcancer cell lines L9981, L9981-pLXSN and L9981-nm23-Hl before and aftertransfection of nm23-Hl gene by Western blot, immunoprecipitation andisotope scintillative count; (2)The proliferative and invasive abilities of theL9981 lung cancer cell line were detected and compared by MTT and
Boyden chamber, before and after transfection of nm23-Hl gene; (3)The changes of expressive level and kinase activities of GSK-3P, P-catenin and phospho-P-catenin were determined in the L9981, L9981-pLXSN and L9981-nm23-Hl lung cancer cell lines before and after treating with GSK-3P kinase inhibitor, LiCL, by Western blot and immunoprecipitation and isotope scintillative count; (4)The effects of GSK-3P kinase inhibitor, LiCL , on the proliferative and invasive activities were detected in L9981, L9981-pLXSN and L9981-nm23-Hl lung cancer cell lines by MTT and Boyden chamber. The result in this study first showed in the world as follows:1.Western blot analysis showed that:(l) The expression of GSK-3P of cytoplasm and nucleus in L9981-nm23-Hl lung cancer cell line was remarkably higher than those in L9981 and L9981-pLXSN lung cancer cell lines (PO.001); (2)The expression of P -catenin of cytoplasm in L9981-nm23-Hl lung cancer cell line was significantly higher than those in L9981 and L9981-pLXSN lung cancer cell lines(P<0.01), but no significant difference of P -catenin expression of nucleus was found among the three lung cancer cell lines; (3)The expression of phospho- P -catenin of necleus in L9981-nm23-Hl cell line was remarkably higher than those in L9981 and L9981-pLXSN cell HnesCPO.OOl), but the expression of phospho- P -catenin of cytoplasm in L9981-nm23-Hl cell line was remarkably lower than those in L9981 and L9981-pLXSN cell lines(/><0.001).2.LiCL is a selective inhibitor of GSK-3P and activitor of Wnt signal pathway. The comparisons of time- and dose-dependent suppression of GSK-3P expression by LiCL showed that the most significant effection of LiCL on GSK-3P expression of cytoplasm and nucleus in the three lung
cancer cell lines was that the cell lines were treated with 20 mmol/L concentration for 60 min.3.After treatment of the three lung cancer cell lines with 20 mmol/L LiCL for 60 min, Western blot analysis showed that:(l) The GSK-3(3 expression of cytoplasm and nucleus in L9981-nm23-Hl lung cancer cell line was remarkably higher than those in L9981 and L9981-pLXSN cell lines (/><0.001);(2) The expression of P -catenin of cytoplasm in L9981-nm23-Hl lung cancer cell line was remarkably lower than those in L9981 and L9981-pLXSN cell lines(P<0.001), but the expression of 3 -catenin of nucleus in L9981-nm23-Hl cell line was significantly higher than those in L9981 and L9981-pLXSN cell lines(P<0.001);(3) The expression of phospho-3 -catenin of necleus in L9981-nm23-Hl cell line was remarkably higher than those in L9981 and L9981-pLXSN cell lines(P<0.001), however, the expression of phospho- P -catenin of cytoplasm in L9981-nm23-Hl cell line was remarkably lower than those in L9981 and L9981-pLXSN cell Iines(P<0.001).4. After treatment of the three cell lines with 20 mmol/L LiCL for 60 min, Western blot analysis showed that:(l)No significant difference of GSK-3p expression of cytoplasm and nucleus in L9981-nm23-Hl cell line was observed betwwen before and after treatment with 20mmol/L LiCL for 60min(P>0.05), but significant down-regulation of GSK-3P expression both in cytoplasm and nucleus was existed in L9981-pLXSN and L9981 cell lines after treatment with 20 mmol/L LiCL for 60 min(P<0.001); (2) P -catenin expression was remarkably increased in L9981-nm23-Hl nucleus and decreased in cytoplasm after treatment with 20mmol/L LiCL for
60min(/><0.001), but the ^ -catenin expression both of cytoplasm and nucleus was significantly upregulated in L9981 and L9981-pLXSN cell lines after treatment with 20 mmol/L for 60 min(.P<0.001); (3)The expression of phospho- P -catenin of cytoplasm and nucleus was downregulated in L9981-nm23-Hl , L9981-pLXSN and L9981 cell lines after treatment with 20mmol/L LiCL for 60min(P<0.001).5.GSK-3P activity assay were detected by immunoprecipitation and isotope scintillative count. GSK-3P activity of cytoplasm and nucleus in L9981-nm23-Hl cell line was remarkably higher than those in L9981 and L9981-pLXSN cell lines (PO.001), but no significant difference was observed between L9981-pLXSN and L9981 cell lines (P>0.05).6.The comparison of time- and dose-dependent suppression showed that: (l)The most significant effection of LiCL on GSK-3P activity in the three cell lines was observed when the cell lines were treated with 20 mmol/L LiCL for 60 min;(2) GSK-3P activity of cytoplasm and nucleus in L9981-nm23-Hl cell line was significantly higher than those in L9981-pLXSN and L9981 cell lines after treatment with 20 mmol/L LiCL for 60 min (P<0.00l), but no significant diffirence of GSK-3P activity of cytoplasm and nucleus was observed between L9981 and L9981-pLXSN cell lines (P>0.05); (3)The activities of GSK-3P both of cytoplasm and nucleus in L9981, L9981-pLXSN and L9981-nm23-Hl lung cancer cell lines after treatment with LiCL were remarkably lower than those before treatment with LiCL (PO.001).7.The cell proliferative and invasive abilities of L9981-nm23-Hl cell line were significantly lower than those in L9981 and L9981-pLXSN cell
lines (PO.001); The cell proliferative and invasive abilities of L9981-nm23-Hl, L9981, and L9981-pLXSN cell lines after treatment with 20 mmol/L LiCL were significantly higher than those before treatment with LiCL (PO.001); The cell proliferative and invasive abilities of L9981-nm23-Hl cell line was still significantly lower than those in L9981 and L9981-pLXSN cell lines after treatment with 20mmol/L LiCL(P<0.001).8.N0 significant difference of GSK-3P expression and activity, P -catenin and phospho- P -catenin expression of cytoplasm and nucleus was existed between L9981 and L9981-pLXSN lung cancer cell lines after treatment with LiCL (P>0.05). There was no significant difference of the proliferation and invasion in L9981 cell line after treatment with LiCL compared with L9981-pLXSN cell line (P>0.05).Conclusion:(l)Transfection of nm23-Hl gene can significantly upregulate the expression and activity of GSK-3p of cytoplasm and nucleus in the human high-metastasis large cell lung cancer cell line L9981; (2)nm23-Hl can significantly upregulate the expression of P -catenin of cytoplasm in the human high-metastasis large cell lung cancer cell line L9981, but not for P -catenin of nucleus; nm23-Hl can also significantly upregulate the expression of phospho-P -catenin of nucleus in L9981 lung cancer cell line; (3) LiCL can not only antagonize the effection of nm23-Hl gene on the upregulation effect for GSK-3p-. P -catenin and phospho- P -catenin in human high metastasis lung cancer cell line L9981, but also antagonize the reversion effects for cell proliferation and invasion of human high metastasis lung cancer cell line L9981. (4)The transduction of Wnt signal might be directly or indirectly suppressed through the upregulation of expression and
activity of GSK-3P in human high-metastasis large cell lung cancer cell lines by nm23-Hl gene. It may be one of the molecular mechanism that nm23-Hl gene regulate "lung cancer metastatic suppressive cascade" and reverse metastatic phenotype of human high-metastasis large cell lung cancer cell lines.
引文
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36. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. CeLL, 2000, 103: 311-320.
37. Satoh S, Daigo Y, Furukawa Y, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat. Genet. 2000; 24: 245-250.
38. Hommura F, Furuuchi K, Yamazaki K, et al. Increased expression of β-catenin predicta better prognosis in non-small cell lung carcinomas. Cancer2002; 94: 752-758.
39. Sunaga N, Kohno T, KolligsFT, et al. Constitutive activation of the Wnt signaling pathway by CTNNB1 (β-catenin) mutations in a subset of human lung adenocarcinoma. Genes Chromosomes Cancer 2001; 30: 316-321.
40. Shigemitsu K, Sekido Y, Usami N, et al. Genetic alteration of the β-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion. Oncogene 2001; 20: 4249-4257.
41. Retera JMAM, Leers MPG, Sulzer MA, et al. The expression of β-catenin in non-small -cell lung cancer: A clinicopathological study. J Clin Pathol 1998; 51: 891-894.
42. Kase S, Sugio K, Yamazaki K, et al. Expression of E-cadherin and β-catenin in human nonsmall cell lung cancer and the clinical significance. Clin Cancer Res 2000; 6: 4789-4796.
43. Hedgepeth C M., Conrad L J, Zhang J, et al. Activation of the Wnt signaling pathway: a molecular mechanism for Lithium action. Development Bioligy. 1997, 185, 82-91.
44. Klein P. S, and Melton D. A. A molecular for the effect of lithium on development. Proc. Natl. Acad. Sci.1996, 93, 8455-8459.
45. Adnan Ali, Klaus P, and James R. W. Glycogen synthase kinase-3: properties, function and regulation. Chem. Rev. 2001, 101: 2527-2540.
46. Sheelagh F, Philip C. GSK3 takes center stage more than 20 years after its discovery. Biochem J, 2001, 359, 1-16.
47. Hartigan, JA, Johnson, GV. Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase 3β-dependent pathway. J Biol Chem, 1999, 274, 21395-21401.
48. Shaw M, and Cohen P. Role of protein kinase B and the MAP kinase cascade in mediating the EGF-dependent inhibition of glycogen synthase kinase 3 in Swiss 3T3 cells. FEBS Lett. 1999, 461, 120-124.
49. He X, Saint-Jeannet J. P, Woodgett J. R, et al. Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature, 1995, 374, 617-622.
50. Troussard AA, Tan C, Yoganalhan TN, et al. Cell-extracellular matrix interaction stimulate the Ap-1 transcription factor in an intergrin-linked kinase and glycogen synthase kinase 3-dependent manner. Mol Cell Biol, 1999, 19: 7420-7427.
51. Takashima A, Noguchi K, Sato K, et al.Tau protein kinase I is essential for amyloid β-protein induced neurotoxicity. Proc Natl Acad Sci, 1993, 90, 7789-7793.
52. Pap M, Cooper, GM. Role of glucose synthase kinase-3 in the phosphatidylinositol 3 kinase/Akt cell survival pathway J Boil Chem, 1998, 273, 19929-19932.
53. Gautam N, Richard S. Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3β. The Journal of Biological Chemistry, 2001, 276: 37436-37442.
54. Yost C, Torres M, Miller J, et al. The axis-inducing activity, stability, and subcellular distribution of β-catenin is regulated in Xenopus embryos by glycogen synthase kinase3. Genes Dev. 1996, 10: 1443-1454.
55. Guo HB, Liu F, Hong J, et al. Down-regulation of N-acetylglucosaminyltransferase V by tumorigenesis or metastasis suppressor gene and its relation to metastatic potential of human hepatocarcinoma cells. J Cell Biochem, 2000, 79(3): 370-385.
56. Iozo RV, Eichsttetter I, Danielson KG. Aberrant expression of the growth factor Wnt-5a in human malignancy.. Can Res, 1995, 55 (16): 3495-3499.
57. Calvo R, West J, Franklin W, et al. Altered HOX and WNT7A expression in human lung cancer. Proc. Natl. Acad. Sci, 2000, 97 (23): 12776-12781.
58. Waltzer L, Bienz M. The control of beta-catenin and TCF during embryonic development and cancer. Cancer and Metastasis Reviews, 1999, 18; 231-246.
59. Pirinen R T, Hirvikoski P, Johansson R T, et al. Reduced expression of α-catenin, β-catenin, and γ-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer. J Clin Pathol, 2001, 54: 391-395.
60. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer, 2002, 2 (3): 161-174.
61. Muller T, Bain G, Wang X, et al. Regulation of epithelial cell migration and tumor formation by β-catenin signaling. Exp Cell Res, 2002, 280 (1): 119-133.
62. Hinck L, Nathke IS, Papkoff J, et al. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J Cell Biol, 1994, 125: 1327-1340.
63. van Noort M, Meeldijik J, van der Zee R, et al. Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem, 2002, 277: 17901-17905.
64. Waltzer L, Bienz M. The control of β-catenin and TCF during embryonic development and cancer. Cancer Metastasis Rev, 1999, 18: 231-246.
65. Chuang GG, Provost E, Kielhorn EP, et al. Tissue microarray analysis of β-catenin in colorectal cancer shows nuclear phospho-β-catenin is associated with a better prognosis. Clin Cancer Res. 2001, 7: 4013-4020.
66. Sadot E, Conacci-Sorrell M, Zhurinsky J, et al. Regulation of S33/S37 phospho-β-catenin in normal and transformed cells. J Cell Sci, 2002, 115: 2771-2780.
67. Thomas P, Khokha R, Shepherd FA, et al. Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. J Pathol, 2000, 190 (2): 150-156.
68. Mei JM, Borchert GL, DonaldSP, et al. Matrix metalloproteinase (s) mediate (s) NO-induced dissociation of β-catenin from membrane bound E-cadherin and formation of nuclear β-catenin/LEF-1 complex. Carcinogenesis, 2002, 23 (12): 2119-2122.
69.车国卫,周清华,张尚福,等.检测肺癌中的微血管密度及其临床意义.中国肺癌杂志,2000,3(4):284-287.
70. Goodwin AM, D Amore PA. Wnt signaling in the vasculature. Angiogenesis, 2002, 5 (1-2): 1-9.
71. Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res, 2001, 61(16): 6050-6054.
72. Holnthoner W, Pillinger M, Groger M, et al. Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells. J Biol Chem, 2002, 277(48): 45847-45853.
73. Weeraratna at, Jiang Y, Hostetter G, et al. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell, 2002, 1(3): 279-288.
74. Hartsough MT, Morrison D K, Salerno M, et al. nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of ras via a histidine protein kinase pathway. J Biol Chem. 2002: 277(35): 32389-32399.
75. Miller JR, Hocking AM, Brown JD, et al. Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways. Oncogene, 1999, 18(55): 7860-7872.
76. Cagatay T, Ozturk M. P53 mutation as a source of aberrant β-catenin accumulation in cancer cells. Oncogene, 2002, 21 (52): 7971-7980.
77.付军科,周清华,朱文,等.nm23-H1基因转染能上调人肺癌细胞株L9981中GSK-3β激酶活性.中国肺癌杂志,2004,7(2):81-85.
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33. Graham AN, Maxwell P, Mulholland K, et al. Increased nm23 immunoreactivity is associated with selective inhibition of systemic tumour cell dissemination. Journal of Clinical Pathology, 2002, 55: 184-189.
34. Nusse R, Varmus H E. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, I982, 31(109): 99-109.
35.梅文燕,丁小燕.Wnt信号途径及其作用机制.生命的化学,2000,5
36. Bienz M, Clevers H. Linking colorectal cancer to Wnt signaling. CeLL, 2000, 103: 311-320.
37. Satoh S, Daigo Y, Furukawa Y, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat. Genet. 2000; 24: 245-250.
38. Hommura F, Furuuchi K, Yamazaki K, et al. Increased expression of β-catenin predicta better prognosis in non-small cell lung carcinomas. Cancer2002; 94: 752-758.
39. Sunaga N, Kohno T, KolligsFT, et al. Constitutive activation of the Wnt signaling pathway by CTNNB1 (β-catenin) mutations in a subset of human lung adenocarcinoma. Genes Chromosomes Cancer 2001; 30: 316-321.
40. Shigemitsu K, Sekido Y, Usami N, et al. Genetic alteration of the β-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion. Oncogene 2001; 20: 4249-4257.
41. Retera JMAM, Leers MPG, Sulzer MA, et al. The expression of β-catenin in non-small -cell lung cancer: A clinicopathological study. J Clin Pathol 1998; 51: 891-894.
42. Kase S, Sugio K, Yamazaki K, et al. Expression of E-cadherin and β-catenin in human nonsmall cell lung cancer and the clinical significance. Clin Cancer Res 2000; 6: 4789-4796.
43. Hedgepeth C M., Conrad L J, Zhang J, et al. Activation of the Wnt signaling pathway: a molecular mechanism for Lithium action. Development Bioligy. 1997, 185, 82-91.
44. Klein P. S, and Melton D. A. A molecular for the effect of lithium on development. Proc. Natl. Acad. Sci.1996, 93, 8455-8459.
45. Adnan Ali, Klaus P, and James R. W. Glycogen synthase kinase-3: properties, function and regulation. Chem. Rev. 2001, 101: 2527-2540.
46. Sheelagh F, Philip C. GSK3 takes center stage more than 20 years after its discovery. Biochem J, 2001, 359, 1-16.
47. Hartigan, JA, Johnson, GV. Transient increases in intracellular calcium result in prolonged site-selective increases in Tau phosphorylation through a glycogen synthase kinase 3β-dependent pathway. J Biol Chem, 1999, 274, 21395-21401.
48. Shaw M, and Cohen P. Role of protein kinase B and the MAP kinase cascade in mediating the EGF-dependent inhibition of glycogen synthase kinase 3 in Swiss 3T3 cells. FEBS Lett. 1999, 461, 120-124.
49. He X, Saint-Jeannet J. P, Woodgett J. R, et al. Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature, 1995, 374, 617-622.
50. Troussard AA, Tan C, Yoganalhan TN, et al. Cell-extracellular matrix interaction stimulate the Ap-1 transcription factor in an intergrin-linked kinase and glycogen synthase kinase 3-dependent manner. Mol Cell Biol, 1999, 19: 7420-7427.
51. Takashima A, Noguchi K, Sato K, et al.Tau protein kinase I is essential for amyloid β-protein induced neurotoxicity. Proc Natl Acad Sci, 1993, 90, 7789-7793.
52. Pap M, Cooper, GM. Role of glucose synthase kinase-3 in the phosphatidylinositol 3 kinase/Akt cell survival pathway J Boil Chem, 1998, 273, 19929-19932.
53. Gautam N, Richard S. Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3β. The Journal of Biological Chemistry, 2001, 276: 37436-37442.
54. Yost C, Torres M, Miller J, et al. The axis-inducing activity, stability, and subcellular distribution of β-catenin is regulated in Xenopus embryos by glycogen synthase kinase3. Genes Dev. 1996, 10: 1443-1454.
55. Guo HB, Liu F, Hong J, et al. Down-regulation of N-acetylglucosaminyltransferase V by tumorigenesis or metastasis suppressor gene and its relation to metastatic potential of human hepatocarcinoma cells. J Cell Biochem, 2000, 79(3): 370-385.
56. Iozo RV, Eichsttetter I, Danielson KG. Aberrant expression of the growth factor Wnt-5a in human malignancy.. Can Res, 1995, 55 (16): 3495-3499.
57. Calvo R, West J, Franklin W, et al. Altered HOX and WNT7A expression in human lung cancer. Proc. Natl. Acad. Sci, 2000, 97 (23): 12776-12781.
58. Waltzer L, Bienz M. The control of beta-catenin and TCF during embryonic development and cancer. Cancer and Metastasis Reviews, 1999, 18; 231-246.
59. Pirinen R T, Hirvikoski P, Johansson R T, et al. Reduced expression of α-catenin, β-catenin, and γ-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer. J Clin Pathol, 2001, 54: 391-395.
60. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer, 2002, 2 (3): 161-174.
61. Muller T, Bain G, Wang X, et al. Regulation of epithelial cell migration and tumor formation by β-catenin signaling. Exp Cell Res, 2002, 280 (1): 119-133.
62. Hinck L, Nathke IS, Papkoff J, et al. Dynamics of cadherin/catenin complex formation: novel protein interactions and pathways of complex assembly. J Cell Biol, 1994, 125: 1327-1340.
63. van Noort M, Meeldijik J, van der Zee R, et al. Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem, 2002, 277: 17901-17905.
64. Waltzer L, Bienz M. The control of β-catenin and TCF during embryonic development and cancer. Cancer Metastasis Rev, 1999, 18: 231-246.
65. Chuang GG, Provost E, Kielhorn EP, et al. Tissue microarray analysis of β-catenin in colorectal cancer shows nuclear phospho-β-catenin is associated with a better prognosis. Clin Cancer Res. 2001, 7: 4013-4020.
66. Sadot E, Conacci-Sorrell M, Zhurinsky J, et al. Regulation of S33/S37 phospho-β-catenin in normal and transformed cells. J Cell Sci, 2002, 115: 2771-2780.
67. Thomas P, Khokha R, Shepherd FA, et al. Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. J Pathol, 2000, 190 (2): 150-156.
68. Mei JM, Borchert GL, DonaldSP, et al. Matrix metalloproteinase (s) mediate (s) NO-induced dissociation of β-catenin from membrane bound E-cadherin and formation of nuclear β-catenin/LEF-1 complex. Carcinogenesis, 2002, 23 (12): 2119-2122.
69.车国卫,周清华,张尚福,等.检测肺癌中的微血管密度及其临床意义.中国肺癌杂志,2000,3(4):284-287.
70. Goodwin AM, D Amore PA. Wnt signaling in the vasculature. Angiogenesis, 2002, 5 (1-2): 1-9.
71. Zhang X, Gaspard JP, Chung DC. Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res, 2001, 61(16): 6050-6054.
72. Holnthoner W, Pillinger M, Groger M, et al. Fibroblast growth factor-2 induces Lef/Tcf-dependent transcription in human endothelial cells. J Biol Chem, 2002, 277(48): 45847-45853.
73. Weeraratna at, Jiang Y, Hostetter G, et al. Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell, 2002, 1(3): 279-288.
74. Hartsough MT, Morrison D K, Salerno M, et al. nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of ras via a histidine protein kinase pathway. J Biol Chem. 2002: 277(35): 32389-32399.
75. Miller JR, Hocking AM, Brown JD, et al. Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways. Oncogene, 1999, 18(55): 7860-7872.
76. Cagatay T, Ozturk M. P53 mutation as a source of aberrant β-catenin accumulation in cancer cells. Oncogene, 2002, 21 (52): 7971-7980.
77.付军科,周清华,朱文,等.nm23-H1基因转染能上调人肺癌细胞株L9981中GSK-3β激酶活性.中国肺癌杂志,2004,7(2):81-85.