干细胞相关因子与胃癌转移的相关性及胃癌卵巢转移手术预后的研究
|
摘要
第一部分干细胞相关因子在胃癌及其远处转移灶中的表达与临床意义
目的：探讨干细胞相关因子与胃癌转移、临床病理参数及预后的关系。
方法：采用SP免疫组化技术检测101例胃癌原发灶及72例胃来源的卵巢转移灶中PcG家族成员Bmi-1、Mel-18、EZH2、CBX7,以及干细胞相关因子Oct4、Sox2、Glil、 CD44、CD133,及其下游靶蛋白p-AKT、p-ERK的表达情况。采用SPSS16.0统计软件,对胃癌原发灶及胃来源的卵巢转移灶上述肿瘤干细胞相关因子的表达的免疫组化结果进行统计分析。胃癌原发灶及胃来源的卵巢转移灶间的表达率情况比较采用x2检验,配对样本表达率比较采用McNemar检验。各临床病理参数与上述肿瘤干细胞相关因子表达情况的关系比较采用x2检验。生存曲线的构建采用Kaplan-Meier方法,评价两曲线的差别有无统计学意义用Log-Rank检验。生存期相关预后因子的多因素分析用Cox回归分析。各肿瘤干细胞相关因子在癌组织中表达的相关性采用Spearman等级相关分析。统计分析中,P<0.05认为差异具有统计学意义,P<0.01认为差异显著。
结果：比较胃癌原发灶及胃来源卵巢转移灶标本中上述干细胞相关因子阳性率的差异,Bmi-1、Oct4、Sox2、Gli1、CD44、CD133、p-AKT、p-ERK在转移灶中阳性表达率显著高于原发灶中阳性表达率；Mel-18在转移灶中阳性表达率低于原发灶中表达,差异均具有统计学意义；CBX7、EZH2在转移灶与原发灶中的表达无显著差异。Bmi-1、EZH2、Oct4、CD44与胃癌淋巴结转移相关。Sox2与胃癌浸润深度相关。EZH2、 Oct4、CD44、CD133与胃癌TNM分期相关。Oct4、CD133与胃癌分化低有关。Oct4表达与胃癌患者年龄较小相关,Sox2表达与胃癌患者性别为男性有关。单因素分析显示,干细胞相关因子(Mel-18、EZH2、Oct4、Sox2、Gli1、CD44)及p-E(?)RK在胃癌原发灶中表达与预后相关。多因素分析显示,CD44与TNM分期是胃癌的独立预后因子。
结论：肿瘤干细胞相关因子Bmi-1, Mel-18, Oct4, Sox2, Gli1, CD44, CD133以及p-AKT、p-ERK与胃癌远处转移相关。CD44及TNM分期为胃癌的独立预后因子。
第二部分胃癌卵巢转移切除术的术前疗效预测及预后分析
目的：通过分析已行胃癌来源的卵巢转移瘤切除术患者预后相关因素,为此类手术术前选择合适的患者提供依据。
方法：共收集133例胃来源的卵巢转移瘤切除术后的患者,进行回顾性分析。采集的临床病理因素包括年龄、胃癌原发病灶与发现卵巢转移的时间关系(同时发现或异时发现)、胃切除手术、卵巢外转移、腹水、卵巢受累(单侧或双侧)、腹盆腔转移、术后残留、术前治疗。生存曲线的构建采用Kaplan-Meier方法,评价两曲线的差别有无统计学意义用Log-Rank检验。生存期相关预后因子的多因素分析用Cox回归分析。并采用分层分析的方法使其更为贴近临床实际。统计分析中,P<0.05认为差异具有统计学意义。所有统计学分析采用SPSS16.0软件进行。
结果：在133例患者中,中位生存时间为16个月(95%CI：13.332-18.668个月)。多因素分析发现腹水(P=0.008)和胃是否切除(P=0.048)是接受卵巢转移手术患者独立的预后因素。分层分析中,腹水仍然是独立的预后因素(P=0.003),且年轻的患者(≤50岁)较年老的患者(>50岁)具有更好的预后(P=0.042)。对于同时性转移的患者,卵巢转移灶和胃癌原发灶均切除者预后较好。
结论：无腹水、接受胃切除术及年龄较轻的患者,从卵巢转移瘤切除术中获益大。反之,不能接受胃切除术、有腹水或者年龄较大的患者,进行卵巢转移瘤切除术需慎重。
Part1Expression and significance of candidate stem cell markers in gastric cancer and its distant metastasis
Object:To investigate the roles of candidate stem cell markers in distant metastasis of human gastric caner, and their correlation with clinic-pathological parameters, prognosis of patients with gastric cancer.
Methods:Immunohistochemistry was used to examine the expression of candidate stem cell markers Bmi-1, Mel-18, EZH2, CBX7, Oct4, Sox2, Gli1, CD44, CD133and their potential downstream tagets p-AKT, p-ERK in samples of gastric cancer primary lesion and distant metastasis. All statistical analyses were performed using the SPSS version16.0software package. The proteins expression difference in gastric primary site and ovarian metastatic lesion were analyzed by χ2-test. McNemar-test was used to compare the protein expression in the matched primary and metastatic case. The χ2-test was also employed to analyze the relationships between the protein expression and clinicopathological factors. Survival curves were estimated using the Kaplan-Meier method, and the differences in survival distributions were evaluated by the log-rank test. The Cox proportional hazards model was used to identify which factors may have a significant influence on survival. The relationship between different factors expression was investigated by Spearman analysis. Differences with a p value of less than0.05were considered to be statistically significant and a value less than0.01were considered to be significant markedly.
Results:The positive rate of Bmi-1, Oct4, Sox2, Gli1, CD44, CD133, p-AKT, p-ERK was significant higher in distant metastasis than in primary lesion of gastric cancer, while the Mel-18reveals the opposite result. The expression EZH2and CBX7showed no significant difference between distant metastasis and primary lesion. The expression of Bmi-1, EZH2, Oct4, CD44were related to lymph node metastasis, and the expression of Sox2was related to the T stage of gastric cancer. The expression of EZH2, Oct4, CD44, CD133correlated with later TNM stage. The expression of Oct4, CD133correlated with differentiation. By using Kaplan-Meier method analysis, the samples with negative expressed of EZH2, Oct4, Sox2, Gli1, CD44, p-ERK or positive expressed of Mel-18acquired better survival of gastric cancer. By using the Cox proportional hazards model, we found out that TNM stage and CD44expression were independent prognostic factors.
Conclusion:Candidate stem cell markers (Bmi-1, Mel-18, Oct4, Sox2, Gli1, CD44, CD133) and p-AKT, p-ERK were related to the distant metastasis of gastric cancer. The factors of TNM stage and CD44expression were possibly the independent prognostic factors of gastric cancer.
Part2Risking factors of metastasectomy for ovary metastasis from gastric cancer
Objective:To determine the risking factors related to the survival of patients who underwent resection of ovarian metastasis from stomach origin and investigate who would benefit from the resection of ovarian metastasis.
Methods:A total of133patients who had undergone resection of ovarian metastasis were retrospectively analyzed. Clinical characteristics including age, synchronous or metachronous ovarian metastasis, gastrectomy, extra-ovarian metastasis, ascites, ovarian involvement (bilateral of unilateral), abdomen-pelvic metastasis, residual disease post resection, treatment before ovarian metastasectomy were indentified. Survival curves were estimated using the Kaplan-Meier method, and the differences in survival distributions were evaluated by the log-rank test. The Cox proportional hazards model was used to identify which factors may have a significant influence on survival. A subgroup analysis was also used. Differences with a p value of less than0.05were considered to be statistically significant. All statistical analyses were performed using the SPSS version16.0software package.
Results:133patients were enrolled in this retrospective study and the median survival time of the patients was16months (95%CI:13.332-18.668months). Multivariate analysis demonstrated that ascites (P=0.008) and gastrectomy (P=0.048) were independent prognostic factors related to survival of patients who underwent resection of ovarian metastasis. Subgroup analysis showed that ascites (P=0.003) was still the independent prognostic factor. Younger patients (≤50years) had the better survival than the elder ones (>50years)(P=0.042). Patients with synchronous metastasis had better prognosis when they recived both gastrectomy and ovarian metastasis surgery.
Conclusions:The patients who did not present ascites, had received gastrectomy before and with low age may benefit from the resection of ovarian metastasis. The ovarian metastasectomy should be decided with cautions when the patients could not receive gastrectomy, present ascites or with advanced age.
目的：探讨干细胞相关因子与胃癌转移、临床病理参数及预后的关系。
方法：采用SP免疫组化技术检测101例胃癌原发灶及72例胃来源的卵巢转移灶中PcG家族成员Bmi-1、Mel-18、EZH2、CBX7,以及干细胞相关因子Oct4、Sox2、Glil、 CD44、CD133,及其下游靶蛋白p-AKT、p-ERK的表达情况。采用SPSS16.0统计软件,对胃癌原发灶及胃来源的卵巢转移灶上述肿瘤干细胞相关因子的表达的免疫组化结果进行统计分析。胃癌原发灶及胃来源的卵巢转移灶间的表达率情况比较采用x2检验,配对样本表达率比较采用McNemar检验。各临床病理参数与上述肿瘤干细胞相关因子表达情况的关系比较采用x2检验。生存曲线的构建采用Kaplan-Meier方法,评价两曲线的差别有无统计学意义用Log-Rank检验。生存期相关预后因子的多因素分析用Cox回归分析。各肿瘤干细胞相关因子在癌组织中表达的相关性采用Spearman等级相关分析。统计分析中,P<0.05认为差异具有统计学意义,P<0.01认为差异显著。
结果：比较胃癌原发灶及胃来源卵巢转移灶标本中上述干细胞相关因子阳性率的差异,Bmi-1、Oct4、Sox2、Gli1、CD44、CD133、p-AKT、p-ERK在转移灶中阳性表达率显著高于原发灶中阳性表达率；Mel-18在转移灶中阳性表达率低于原发灶中表达,差异均具有统计学意义；CBX7、EZH2在转移灶与原发灶中的表达无显著差异。Bmi-1、EZH2、Oct4、CD44与胃癌淋巴结转移相关。Sox2与胃癌浸润深度相关。EZH2、 Oct4、CD44、CD133与胃癌TNM分期相关。Oct4、CD133与胃癌分化低有关。Oct4表达与胃癌患者年龄较小相关,Sox2表达与胃癌患者性别为男性有关。单因素分析显示,干细胞相关因子(Mel-18、EZH2、Oct4、Sox2、Gli1、CD44)及p-E(?)RK在胃癌原发灶中表达与预后相关。多因素分析显示,CD44与TNM分期是胃癌的独立预后因子。
结论：肿瘤干细胞相关因子Bmi-1, Mel-18, Oct4, Sox2, Gli1, CD44, CD133以及p-AKT、p-ERK与胃癌远处转移相关。CD44及TNM分期为胃癌的独立预后因子。
第二部分胃癌卵巢转移切除术的术前疗效预测及预后分析
目的：通过分析已行胃癌来源的卵巢转移瘤切除术患者预后相关因素,为此类手术术前选择合适的患者提供依据。
方法：共收集133例胃来源的卵巢转移瘤切除术后的患者,进行回顾性分析。采集的临床病理因素包括年龄、胃癌原发病灶与发现卵巢转移的时间关系(同时发现或异时发现)、胃切除手术、卵巢外转移、腹水、卵巢受累(单侧或双侧)、腹盆腔转移、术后残留、术前治疗。生存曲线的构建采用Kaplan-Meier方法,评价两曲线的差别有无统计学意义用Log-Rank检验。生存期相关预后因子的多因素分析用Cox回归分析。并采用分层分析的方法使其更为贴近临床实际。统计分析中,P<0.05认为差异具有统计学意义。所有统计学分析采用SPSS16.0软件进行。
结果：在133例患者中,中位生存时间为16个月(95%CI：13.332-18.668个月)。多因素分析发现腹水(P=0.008)和胃是否切除(P=0.048)是接受卵巢转移手术患者独立的预后因素。分层分析中,腹水仍然是独立的预后因素(P=0.003),且年轻的患者(≤50岁)较年老的患者(>50岁)具有更好的预后(P=0.042)。对于同时性转移的患者,卵巢转移灶和胃癌原发灶均切除者预后较好。
结论：无腹水、接受胃切除术及年龄较轻的患者,从卵巢转移瘤切除术中获益大。反之,不能接受胃切除术、有腹水或者年龄较大的患者,进行卵巢转移瘤切除术需慎重。
Part1Expression and significance of candidate stem cell markers in gastric cancer and its distant metastasis
Object:To investigate the roles of candidate stem cell markers in distant metastasis of human gastric caner, and their correlation with clinic-pathological parameters, prognosis of patients with gastric cancer.
Methods:Immunohistochemistry was used to examine the expression of candidate stem cell markers Bmi-1, Mel-18, EZH2, CBX7, Oct4, Sox2, Gli1, CD44, CD133and their potential downstream tagets p-AKT, p-ERK in samples of gastric cancer primary lesion and distant metastasis. All statistical analyses were performed using the SPSS version16.0software package. The proteins expression difference in gastric primary site and ovarian metastatic lesion were analyzed by χ2-test. McNemar-test was used to compare the protein expression in the matched primary and metastatic case. The χ2-test was also employed to analyze the relationships between the protein expression and clinicopathological factors. Survival curves were estimated using the Kaplan-Meier method, and the differences in survival distributions were evaluated by the log-rank test. The Cox proportional hazards model was used to identify which factors may have a significant influence on survival. The relationship between different factors expression was investigated by Spearman analysis. Differences with a p value of less than0.05were considered to be statistically significant and a value less than0.01were considered to be significant markedly.
Results:The positive rate of Bmi-1, Oct4, Sox2, Gli1, CD44, CD133, p-AKT, p-ERK was significant higher in distant metastasis than in primary lesion of gastric cancer, while the Mel-18reveals the opposite result. The expression EZH2and CBX7showed no significant difference between distant metastasis and primary lesion. The expression of Bmi-1, EZH2, Oct4, CD44were related to lymph node metastasis, and the expression of Sox2was related to the T stage of gastric cancer. The expression of EZH2, Oct4, CD44, CD133correlated with later TNM stage. The expression of Oct4, CD133correlated with differentiation. By using Kaplan-Meier method analysis, the samples with negative expressed of EZH2, Oct4, Sox2, Gli1, CD44, p-ERK or positive expressed of Mel-18acquired better survival of gastric cancer. By using the Cox proportional hazards model, we found out that TNM stage and CD44expression were independent prognostic factors.
Conclusion:Candidate stem cell markers (Bmi-1, Mel-18, Oct4, Sox2, Gli1, CD44, CD133) and p-AKT, p-ERK were related to the distant metastasis of gastric cancer. The factors of TNM stage and CD44expression were possibly the independent prognostic factors of gastric cancer.
Part2Risking factors of metastasectomy for ovary metastasis from gastric cancer
Objective:To determine the risking factors related to the survival of patients who underwent resection of ovarian metastasis from stomach origin and investigate who would benefit from the resection of ovarian metastasis.
Methods:A total of133patients who had undergone resection of ovarian metastasis were retrospectively analyzed. Clinical characteristics including age, synchronous or metachronous ovarian metastasis, gastrectomy, extra-ovarian metastasis, ascites, ovarian involvement (bilateral of unilateral), abdomen-pelvic metastasis, residual disease post resection, treatment before ovarian metastasectomy were indentified. Survival curves were estimated using the Kaplan-Meier method, and the differences in survival distributions were evaluated by the log-rank test. The Cox proportional hazards model was used to identify which factors may have a significant influence on survival. A subgroup analysis was also used. Differences with a p value of less than0.05were considered to be statistically significant. All statistical analyses were performed using the SPSS version16.0software package.
Results:133patients were enrolled in this retrospective study and the median survival time of the patients was16months (95%CI:13.332-18.668months). Multivariate analysis demonstrated that ascites (P=0.008) and gastrectomy (P=0.048) were independent prognostic factors related to survival of patients who underwent resection of ovarian metastasis. Subgroup analysis showed that ascites (P=0.003) was still the independent prognostic factor. Younger patients (≤50years) had the better survival than the elder ones (>50years)(P=0.042). Patients with synchronous metastasis had better prognosis when they recived both gastrectomy and ovarian metastasis surgery.
Conclusions:The patients who did not present ascites, had received gastrectomy before and with low age may benefit from the resection of ovarian metastasis. The ovarian metastasectomy should be decided with cautions when the patients could not receive gastrectomy, present ascites or with advanced age.
引文
[1]Jemal A, Bray F, Center MM, et al. Global cancer statistics[J]. CA Cancer J Clin,2011,61(2):69-90.
[2]Yang L. Incidence and mortality of gastric cancer in China[J]. World J Gastroenterol,2006,12(1): 17-20.
[3]Krumlauf R. Hox genes in vertebrate development[J]. Cell,1994,78(2):191-201.
[4]Jacobs JJ, van Lohuizen M. Polycomb repression:from cellular memory to cellular proliferation and cancer[J]. Biochim Biophys Acta,2002,1602(2):151-61.
[5]Takaishi S, Okumura T, Tu S, et al. Identification of gastric cancer stem cells using the cell surface marker CD44[J]. Stem Cells,2009,27(5):1006-20.
[6]Levine SS, King IF, Kingston RE. Division of labor in polycomb group repression[J]. Trends Biochem Sci,2004,29(9):478-85.
[7]Ringrose L, Paro R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins[J]. Annu Rev Genet,2004,38:413-43.
[8]Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer, the polycomb connection[J]. Cell,2004,118(4):409-18.
[9]Chamberlain SJ, Yee D, Magnuson T. Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells,2008,26(6):1496-505.
[10]Pereira CF, Piccolo FM, Tsubouchi T, et al. ESCs require PRC2 to direct the successful reprogramming of differentiated cells toward pluripotency[J]. Cell Stem Cell,2010,6(6):547-56.
[11]Haupt Y, Alexander WS, Barri G, et al. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice[J], Cell,1991,65(5):753-63.
[12]Alkema MJ, Wiegant J, Raap AK, et al. Characterization and chromosomal localization of the human proto-oncogene BMI-1[J]. Hum Mol Genet,1993,2(10):1597-603.
[13]Alkema MJ, Bronk M, Verhoeven E, et al. Identification of Bmil-interacting proteins as constituents of a multimeric mammalian polycomb complex[J]. Genes Dev,1997,11(2):226-40.
[14]van der Lugt NM, Domen J, Linders K, et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene[J]. Genes Dev,1994,8(7):757-69.
[15]Jacobs JJ, Kieboom K, Marino S, et al. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus[J]. Nature,1999,397(6715):164-8.
[16]van Lohuizen M, Frasch M, Wientjens E, et al. Sequence similarity between the mammalian bmi-1 proto-oncogene and the Drosophila regulatory genes Psc and Su(z)2[J]. Nature,1991,353(6342):353-5.
[17]Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells[J]. Nature,2003,423(6937):255-60.
[18]Kim JH, Yoon SY, Kim CN, et al. The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p161NK4a/p14ARF proteins[J]. Cancer Lett,2004,203(2): 217-24.
[19]Dimri GP, Martinez JL, Jacobs JJ, et al. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells[J]. Cancer Res.2002,62(16):4736-45.
[20]Kim JH, Yoon SY, Jeong SH, et al. Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer[J]. Breast,2004,13(5):383-8.
[21]Mihic-Probst D, Kuster A, Kilgus S, et al. Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma[J]. Int J Cancer,2007,121(8):1764-70.
[22]黄开红,刘建化,李学先,et al. Bmi-1在胃癌组织中的表达及相关性研究[J].中国肿瘤临床,2007,34(17)：961-965.
[23]Liu JH, Song LB, Zhang X, et al. Bmi-1 expression predicts prognosis for patients with gastric carcinoma[J]. J Surg Oncol,2008,97(3):267-72.
[24]Zhang XW, Sheng YP, Li Q, et al. BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer[J]. Mol Cancer,9:40.
[25]Song LB, Zeng MS, Liao WT, et al. Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells[J]. Cancer Res, 2006,66(12):6225-32.
[26]Choi YJ, Choi YL, Cho EY, et al. Expression of Bmi-1 protein in tumor tissues is associated with favorable prognosis in breast cancer patients[J]. Breast Cancer Res Treat,2009,113(1):83-93.
[27]Asano H, Ishida A, Hasegawa M, et al. The mouse Mel-18 "RING-finger" gene:genomic organization, promoter analysis and chromosomal assignment[J]. DNA Seq,1993,3(6):369-77.
[28]Goebl MG. The bmi-1 and mel-18 gene products define a new family of DNA-binding proteins involved in cell proliferation and tumorigenesis[J]. Cell,1991,66(4):623.
[29]Akasaka T, Kanno M, Balling R, et al. A role for mel-18, a Polycomb group-related vertebrate gene, during theanteroposterior specification of the axial skeleton[J]. Development,1996,122(5):1513-22.
[30]Elderkin S, Maertens GN, Endoh M, et al. A phosphorylated form of Mel-18 targets the Ring1B histone H2A ubiquitin ligase to chromatin[J]. Mol Cell,2007,28(1):107-20.
[31]Kanno M, Hasegawa M, Ishida A, et al. Mel-18, a Polycomb group-related mammalian gene, encodes a transcriptional negative regulator with tumor suppressive activity[J]. EMBO J,1995,14(22): 5672-8.
[32]Wiederschain D, Chen L, Johnson B, et al. Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis[J]. Mol Cell Biol,2007,27(13):4968-79.
[33]Guo WJ, Datta S, Band V, Dimri GP. Mel-18, a polycomb group protein, regulates cell proliferation and senescence via transcriptional repression of Bmi-1 and c-Myc oncoproteins[J]. Mol Biol Cell,2007, 18(2):536-46.
[34]Tetsu O, Ishihara H, Kanno R, et al. mel-18 negatively regulates cell cycle progression upon B cell antigen receptor stimulation through a cascade leading to c-myc/cdc25[J]. Immunity,1998,9(4):439-48.
[35]Chun T, Rho SB, Byun HJ, et al. The polycomb group gene product Mel-18 interacts with cyclin D2 and modulates its activity[J]. FEBS Lett,2005,579(24):5275-80.
[36]Guo BH, Zhang X, Zhang HZ, et al. Low expression of Mel-18 predicts poor prognosis in patients with breast cancer. Ann Oncol,2010,21(12):2361-9.
[37]Wang W, Lin T, Huang J, et al. Analysis of Mel-18 expression in prostate cancer tissues and correlation with clinicopathologic features[J]. Urol Oncol,2009,29(3):244-51.
[38]Lu YW, Li J, Guo WJ. Expression and clinicopathological significance of Mel-18 and Bmi-1 mRNA in gastric carcinoma[J]. J Exp Clin Cancer Res,2010,29:143.
[39]Hobert O, Jallal B, Ullrich A. Interaction of Vav with ENX-1 a putative transcriptional regulator of homeobox gene expression [J]. Mol Cell Biol,1996,16(6):3066-3073
[40]Cardoso C, Mignon C, Hetet G, et al. The human EZH2 gene:genomic organisation and revised mapping in 7q35 within the critical region for malignant myeloid disorders[J]. Eur J Hum Genet,2000, 8(3):174-80.
[41]Kondo Y, Shen L, Cheng AS, et al. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation[J]. Nat Genet,2008,40(6):741-50.
[42]Lee TI, Jenner RG, Boyer LA, et al. Control of developmental regulators by Polycomb in human embryonic stem cells[J]. Cell,2006,125(2):301-13.
[43]Plath K, Fang J, Mlynarczyk-Evans SK, et al. Role of histone H3 lysine 27 methylation in X inactivation[J]. Science,2003,300(5616):131-5.
[44]Caretti G, Di Padova M, Micales B, et al. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation[J]. Genes Dev,2004,18(21):2627-38.
45 Suva ML, Riggi N, Janiszewska M, et al. EZH2 is essential for glioblastoma cancer stem cell maintenance[J]. Cancer Res,2009,69(24):9211-8.
[46]Chen Y, Lin MC, Yao H, et al. Lentivirns. mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin [J]. Hepatology,2007,46(1):200.
[47]Fujii S, Ochiai A. Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells[J]. Cancer Sci,2008,99(4):738-746.
[48]Wang C, Liu X, Chen Z, et al. Polycomb group protein EZH2-mediated E-cadherin repression promotes metastasis of oral tongue squamous cell carcinoma[J]. Mol Carcinog,2011.
[49]Bracken AP, Pasini D, Capra M, et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer[J]. EMBO J,2003,22(20):5323-5335.
[50]Rajasekhar VK, Begemann M. Concise review:roles of polycomb group proteins in development and disease:a stem cell perspective[J]. Stem Cells,2007,25(10):2498-510.
[51]Rao ZY, Cai MY, Yang GF, et al. EZH2 supports ovarian carcinoma cell invasion and/or metastasis via regulation of TGF-betal and is a predictor of outcome in ovarian carcinoma patients[J]. Carcinogenesis.2010,31(9):1576-83.
[52]Matsukawa Y, Semba S, Kato H, et al. Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer[J]. Cancer Sci.2006,97(6):484-91.
[53]苗芳,李劲松.EZHZ和Ki-67在胃癌中的表达及其临床意义[J].泰山医学院学报,2008,29(2)：87-89.
[54]Kleer CG, Can Q, Varambal]y S, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells [J]. Proc Nail Acad Sci USA,2003,100(20): 11606-11611.
[55]Mattioli E, Vogiatzi P, Sun A, et al. Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, pl6(INK4A), p27(KIP1), p21(WAF1), Ki-67 expression patterns in gastric cancer[J]. J Cell Physiol. 2007,210(1):183-91.
[56]Sudo T, Utsunomiya T, Mimori K, et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma[J]. Br J Cancer.2005,92(9):1754-8.
[57]Chen Y, Xie D, Yin Li W, et al. RNAi targeting EZH2 inhibits tumor growth and liver metastasis of pancreatic cancer in vivo[J]. Cancer Lett.2010,297(1):109-16.
[58]Fluge, et al. Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis[J]. British Journal of Cancer (2009) 101,1282-1289.
[59]Ciarapica R, Russo G, Verginelli F, et al. Deregulated expression of miR-26a and Ezh2 in rhabdomyosarcoma[J]. Cell Cycle.2009,8(1):172-5.
[60]Mimori K, Ogawa K, Okamoto M, et al. Clinical significance of enhancer of zeste homolog 2 expression in colorectal cancer cases[J]. Eur J Surg Oncol.2005,31(4):376-80.
[61]Gil J, Bernard D, Martinez D, et al. Polycomb CBX7 has a unifying role in cellular lifespan[J]. Nat Cell Biol,2004,6(1):67-72.
[62]Scott CL, Gil J, Hernando E, et al. Role of the chromobox protein CBX7 in lymphomagenesis[J]. Proc Natl Acad Sci U S A.2007,104(13):5389-94.
[63]Zhang XW, Zhang L, Qin W, et al. Oncogenic role of the chromobox protein CBX7 in gastric cancer[J]. J Exp Clin Cancer Res.2010,29:114.
[64]Karamitopoulou E, Pallante P, Zlobec I, et al. Loss of the CBX7 protein expression correlates with a more aggressive phenotype in pancreatic cancer[J]. Eur J Cancer.46(8):1438-44.
[65]管振坡,谷连坤,邢宝才,et al.色素框同源蛋白7基因在人体多种癌组织中表达下调[J].中华预防医学杂志,2011,45(7).
[66]Pallante P, Federico A, Berlingieri MT, et al. Loss of the CBX7 gene expression correlates with a highly malignant phenotype in thyroid cancer[J]. Cancer Res.2008,68(16):6770-6778.
[67]Hinz S, Kempkensteffen C, Christoph F, et al. Expression parameters of the polycomb group proteins BMI1, SUZ12, RING1 and CBX7 in urothelial carcinoma of the bladder and their prognostic relevanceTumor [J]. Biol.2008,29:323-329.
[68]Herr W, Cleary MA. The POU domain:versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain[J]. Genes Dev.1995,9(14):1679-93.
[69]Scholer HR, Balling R, Hatzopoulos AK, et al. Octamer binding proteins confer transcriptional activity in early mouse embryogenesis[J]. EMBO J.1989,8(9):2551-7.
[70]Rodriguez R T, Velkey J M, Lutzko C, et al. Manipulation of Oct4 levels in human embryonic stem cells results in induction of differential cell types [J]. Exp Biol Med,2007,232(10):1368-1380.
[71]Yu J, Vodyanik M A, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells [J]. Science,2007,318(5858):1917-1920.
[72]Gu P, Le Menuet D, Chung AC, et al. Differential recruitment of methylated CpG binding domains by the orphan receptor GCNF initiates the repression and silencing of Oct4 expression[J]. Mol Cell Biol. 2006,26(24):9471-83.
[73]Melchior K, Weiss J, Zaehres H, et al. The WNT receptor FZD7 contributes self-renewal signaling of human embryonic stem cells [J]. Biol Chem,2008,389(7):897-903.
[74]Liu CG, Lu Y, Wang BB, et al. Clinical implications of stem cell gene Oct-4 expression in breast cancer[J]. Ann Surg.2011,253(6):1165-71.
[75]Chen YC, Hsu HS, Chen YW, et al. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells[J]. PLoS One.2008,3(7):e2637.
[76]Chiou SH, Wang ML, Chou YT, et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation[J]. Cancer Res.2010,70(24):10433-44.
[77]Zito G, Richiusa P, Bommarito A, et al. In vitro identification and characterization of CD133(pos) cancer stem-like cells in anaplastic thyroid carcinoma cell lines[J]. PLoS One.2008,3(10):e3544.
[78]Xu XL, Xing BC, Han HB, et al. The properties of tumor-initiating cells from a hepatocellular carcinoma patient's primary and recurrent tumor[J]. Carcinogenesis.31(2):167-74.
[79]Zhang Y, Peng J, Zhang H, et al. Notch1 signaling is activated in cells expressing embryonic stem cell proteins in human primary nasopharyngeal carcinoma[J]. J Otolaryngol Head Neck Surg.2010, 39(2):157-66.
[80]Yuan F, Zhou W, Zou C, et al. Expression of Oct4 in HCC and modulation to wnt/beta-catenin and TGF-beta signal pathways. Mol Cell Biochem[J].2010,343(1-2):155-62.
[81]Ong CW, Kim LG, Kong HH, et al. CD133 expression predicts for non-response to chemotherapy in colorectal cancer[J]. Mod Pathol.2010,23(3):450-7.
[82]姚宏亮,杨竹林,李永国,et al.胃良恶性病变组织中PSCA和Oct-4的表达及意义[J].中南大学学报(医学版),2008,8.
[83]Chen Z, Xu WR, Qian H, et al. Oct4, a novel marker for human gastric cancer[J].J Surg Oncol. 2009,99(7):414-9.
[84]Sinclair AH, Berta P, Palmer MS, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif[J]. Nature.1990,346(6281):240-4.
[85]Wegner M. From head to toes:the multiple facets of Sox proteins[J]. Nucleic Acids Res.1999,27(6): 1409-20.
[86]Zhang W, Glockner SC, Guo M, et al. Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer[J]. Cancer Res.2008,68(8):2764-72.
[87]Harley VR, Lovell-Badge R, Goodfellow PN. Definition of a consensus DNA binding site for SRY[J]. Nucleic Acids Res.1994,22(8):1500-1.
[88]Chew JL, Loh YH, Zhang W, et al. Reciprocal transcriptional regulation of Pou5fl and Sox2 via the Oct4/Sox2 complex in embryonic stem cells[J]. Mol Cell Biol.2005,25(14):6031-46.
[89]Chen Y, Shi L, Zhang L, et al. The molecular mechanism governing the oncogenic potential of Sox2 in breast cancer[J]. J Biol Chem.2008,283(26):17969-78.
[90]Ye F, Li Y, Hu Y, et al.. Expression of Sox2 in human ovarian epithelial carcinoma. J Cancer Res Clin Oncol[J].2010,137(1):131-7.
[91]Mutoh H, Sashikawa M, Sugano K. Sox2 expression is maintained while gastric phenotype is completely lost in Cdx2-induced intestinal metaplastic mucosa[J]. Differentiation.2010,81(2):92-8.
[92]Li XL, Eishi Y, Bai YQ, et al. Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma[J]. Int J Oncol,2004.24(2):257-63.
[93]Qi H, Pei D. The magic of four:induction of pluripotent stem cells from somatic cells by Oct4, Sox2, Myc and Klf4[J]. Cell Res.2007,17(7):578-80.
[94]Otsubo T, Akiyama Y, Yanagihara K, et al. Sox2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis[J]. Br J Cancer,2008,98(4):824-831.
[95]Zhang X, Yu H, Yang Y, et al, Sox2 in gastric carcinoma, but not Hathl, is related to patients' clinicopathological features and prognosis[J]. J Gastrointest Surg.2010,14(8):1220-6.
[96]Matsuoka J, Yashiro M, Sakurai K, et al., Role of the Sternness Factors Sox2, Oct3/4, and Nanog in Gastric Carcinoma[J]. J Surg Res,2010.
[97]Kinzler KW, Bigner SH, Bigner DD, et al. Identification of an amplified, highly expressed gene in a human glioma. Science[J].1987,236(4797):70-3.
[98]Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis[J]. Nature.2004(7009),431:707-12.
[99]Machold R, Hayashi S, Rutlin M, et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches[J]. Neuron.2003,39(6):937-50.
[100]Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells[J]. Cancer Res.2006,66(12):6063-71.
[101]Peacock CD, Wang Q, Gesell GS, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma[J]. Proc Natl Acad Sci U S A.2007,104(10):4048-53.
[102]Clement V, Sanchez P, de Tribolet N, et al. HEDGEHOG-Glil signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity[J]. Curr Biol.2007,17(2):165-72.
[103]鲁智豪,贾军,任军,etal.乳腺癌干细胞的检测及Hedgehog信号通路关键分子的表达[J].北京大学学报(医学版),2008,5,480-485.
[104]Song Z, Yue W, Wei B, et al. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer[J]. PLos One,2011,6(3):e17687.
[105]Lupi O. Correlations between the sonic hedgehog pathway and basal cell carcinoma[J]. Int J Dermatol,2007,46(11):1113-7
[106]Sengupta A, Banerjee D, Chandra S, et al. Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression[J]. Leukemia.2007,21 (5):949-55.
[107]Stecca B, Mas C, Clement V, et al. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between Glil and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A[J].2007, 104(14):5895-900.
[108]Dennler S, Andre J, Alexaki I, et al. Induction of sonic hedgehog mediators by transforming growth factor-beta:Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res[J]. 2007,67(14):6981-6.
[109]Rao G, Pedone CA, Coffin CM, et al. c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice[J]. Neoplasia.2003,5(3):198-204.
[110]Stecca B, Ruiz i Altaba A. A Glil-p53 inhibitory loop controls neural stem cell and tumour cell numbers[J]. EMBO J.2009,28(6):663-76.
[111]Yoo YA, Kang MH, Kim JS, et al. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway[J]. Carcinogenesis.2008,29(3):480-90.
[112]Das S, Harris LG, Metge BJ, et al. The hedgehog pathway transcription factor Gli1 promotes malignant behavior of cancer cells by up-regulating osteopontin[J]. J Biol Chem.2009,284(34): 22888-97.
[113]Fernandez-Zapico ME. Primers on molecular pathways GLI:more than just Hedgehog? [J] Pancreatology.2008,8(3):227-9.
[114]Ohta M, Tateishi K, Kanai F, et al. p53-Independent negative regulation of p21/cyclin-dependent kinase-interacting protein 1 by the sonic hedgehog-glioma-associated oncogene 1 pathway in gastric carcinoma cells[J]. Cancer Res.2005,65(23):10822-9.
[115]Ma X, Chen K, Huang S, et al. Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas[J]. Carcinogenesis.2005,26(10):1698-705.
[116]Yanai K, Nagai S, Wada J, et al. Hedgehog signaling pathway is a possible therapeutic target for gastric cancer[J]. J Surg Oncol.2007,95(1):55-62.
[117]Chatel G, Ganeff C, Boussif N, et al. Hedgehog signaling pathway is inactive in colorectal cancer cell lines[J]. Int J Cancer.2007,121(12):2622-7.
[118]Feldmann G, Habbe N, Dhara S, et al. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer[J]. Gut.2008,57(10):1420-30.
[119]Choi CH, Roh CR, Kim TJ, et al. Expression of CD44 adhesion molecules on human placentae[J]. Eur J Obstet Gynecol Reprod Biol.2006,128(1-2):243-7.
[120]Honeth G, Bendahl PO, Ringner M, et al. The CD44+/CD24-phenotype is enriched in basal-like breast tumors[J]. Breast Cancer Res.2008,10(3):R53.
[121]Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells [J]. Cancer Res, 2007,67(3):1030-1037.
[122]Pham PY, Phan NL, Nguyen NT, et al. Differentiation of breast cancer stem cells by knockdown of CD44:promising differentiation therapy[J]. J Transl Med.2011,9:209.
[123]Rocco A, Liguori E, Pirozzi G, et al. CD133 and CD44 Cell surface markers do not identify cancer stem cells in primary human gastric tumors[J]. J Cell Physiol.2012,227(6):2686-93.
[124]Lee JL, Wang MJ, Sudhir PR, et al. Osteopontin promotesintegrin activation through outside-in and inside-out mechanism:OPN-CD44v interaction enhances survival in gastrointestinal cancer cells[J]. Cancer Res,2007,67:2089.
[125]Wielenga VJ, Smits R, Korinek V, et al. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway[J]. Am J Pathol,1999,154:515.
[126]Zhu D, Bourguignon LY. Interaction between CD44 and the repeat domain of ankyrin promotes hyaluronic acid-mediated ovarian tumor cell migration[J]. J Cell Physiol,2000,183(2):182-95.
[127]Li CZ, Liu B, Wen ZQ, et al. Inhibition of CD44 expression by small interfering RNA to suppress the growth and metastasis of ovarian cancer cells in vitro and in vivo[J]. Folia Biol (Praha).2008,54(5): 180-6.
[128]Ghaffarzadehgan K, Jafarzadeh M, Raziee HR, et al. Expression of cell adhesion molecule CD44 in gastric adenocarcinoma and its prognostic importance[J]. World J Gastroenterol.2008, 14(41):6376-81.
[129]王庆才,高阳,侯刚,et al.应用组织芯片技术检测胃癌组织中抑癌基因、环氧合酶4和CD44的表达[J].中华消化杂志,2007,4,27(4),280.
[130]Nishii T, Yashiro M, Shinto O, et al. Cancer stem cell-like SP cells have a high adhesion ability to the peritoneum in gastric carcinoma[J]. Cancer Sci,2009,100(8):1397
[131]Heridan C, Kis himot o H, Fuchs RK, et al. CD44+/CD24-breast cancer cells exhibit enhanced in vasive properties:an early step necessary for metastasis [J]. Breast C ancer Res 2006,8(5):R59.
[132]Balic M, Lin H, Young L, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have putative breast cancer stem cell phenotype[J]. Clin Cancer Res,2006, 12(19):5615-5621.
[133]Amirghofran Z, Jalali SA, Hosseini SV, et al. Evaluation of CD44 and CD44v6 in colorectal carcinoma patients:soluble forms in relation to tumor tissue expression and metastasis[J]. J Gastrointest Cancer.2008,39(1-4):73-8.
[134]Kunimura T, Yoshida T, Sugiyama T, et al. The Relationships Between Loss of Standard CD44 Expression and Lymph Node, Liver Metastasis in T3 Colorectal Carcinoma[J]. J Gastrointest Cancer. 2009,40(3-4):115-8.
[135]ISongun, SV Litvinov, CJH van de Velde, et al. Loss of Ep-CAM(CO17-1A) expression predicts survival in patients with gastric cancer[J]. British Journal of Cancer,2005,92(9):1767.
[136]Yin AH, Miraglia S, Zanjani ED, et al. AC 133, a novel marker for human hematopoietic stem and progenitor cells[J]. Blood.1997,90(12):5002-12.
[137]Gordon PR, Leimig T, Babarin-Dorner A, et al. Large-scale isolation of CD133+ progenitor cells from G-CSF mobilized peripheral blood stem cells[J]. Bone Marrow Transplant.2003,31(1):17-22.
[138]Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells[J]. Nature.2004,432(7015):396-401.
[139]Liu G, Yuan X, Zeng Z, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma[J]. Mol Cancer.2006,5(5):67.
[140]O'Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice[J]. Nature.2007,445(7123):106-10.
[141]Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer[J]. Cell Stem Cell.2007,1(3):313-23.
[142]Smith LM, Nesterova A, Ryan MC, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers[J]. Br J Cancer.2008,99(1):100-9.
[143]Karbanova J, Missol-Kolka E, Fonseca AV, et al. The stem cell marker CD 133 (Prominin-1) is expressed in various human glandular epithelia[J]. J Histochem Cytochem.2008,56(11):977-93.
[144]Ulasov Ⅳ, Nandi S, Dey M, et al. Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+)glioma stem cells to temozolomide therapy[J]. Mol Med.2010,17(1-2):103-12.
[145]Deng YH, Pu XX, Huang MJ, et al.5-Fluorouracil upregulates the activity of Wnt signaling pathway in CD133-positive colon cancer stem-like cells[J]. Chin J Cancer.2010,29(9):810-5.
[146]唐毕峰,马立业,瞿羽佳,et al.肿瘤干细胞标志物CD133在胃癌中的表达及其临床意义[J].临床肿瘤学杂志,2008,13(6)：495-498.
[147]Ishigami S, Ueno S, Arigami T, et al. Prognostic impact of CD133 expression in gastric carcinoma. Anticancer Res[J].2010,30(6):2453-7.
[148]Wakamatsu Y, Sakamoto N, Oo HZ, et al. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer[J]. Pathol Int.2012,62(2): 112-9.
[149]Mehra N, Penning M, Maas J, et al. Progenitor marker CD 133 mRNA is elevated in peripheral blood of cancer patients with bone metastases[J]. Clin Cancer Res.2006,12(16):4859-66.
[150]Huang X, Sheng Y, Guan M. Co-expression of stem cell genes CD 133 and CD44 in colorectal cancers with early liver metastasis[J]. Surg Oncol,2011.
[151]Boegl M, Prinz C. CD133 expression in different stages of gastric adenocarcinoma[J]. Br J Cancer. 2009,100(8):1365-6, author reply 7.
[152]Lee SH, Kim HS, Park WS, et al. Non-small cell lung cancers frequently express phosphorylated AKT, an immunohistochemical study[J].2002,110(7-8):587-92.
[153]Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/AKT pathway promotestranslocation of Mdm2 from the cytoplasm to the nucleus[J]. Proc Natl Acad Sci U S A.2001,98(20):11598-603.
[154]Grille SJ, Bellacosa A, Upson J, et al. The protein kinase AKT induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines[J]. Cancer Res.2003,63(9):2172-8.
[155]Tazzari PL, Cappellini A, Ricci F, et al. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/AKT signal transduction network in human acute myelogenous leukemia blasts[J]. Leukemia.2007,21(3):427-38.
[156]Cinti C, Vindigni C, Zamparelli A, et al. Activated AKT as an indicator of prognosis in gastric cancer[J]. Virchows Arch.2008,453(5):449-55.
[157]Nam SY, Lee HS, Jung GA, et al. AKT/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis[J]. APMIS.2003,111(12):1105-13.
[158]David O, Jett J, LeBeau H, et al. Phospho-AKT overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage[J]. Clin Cancer Res.2004,10(20):6865-71.
[159]Massion PP, Taflan PM, Shyr Y, et al. Early involvement of the phosphatidylinositol 3-kinase/AKT pathway in lung cancer progression[J]. Am J Respir Crit Care Med.2004,170(10):1088-94.
[160]Li J, Wang G, Wang C, et al. MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal [J]. Differentiation.2007,75(4):299-307.
[161]许春进,陈玉龙,韩敏,et al.转化生长因子β1和磷酸化细胞外信号调节激酶在胃癌中的表达[J].中华内科杂志,2006,45(7),586-7.
[162]董慧明,刘刚,吴炅,et al. MAPK信号传导通路对人炎性乳腺癌细胞系侵袭能力的影响[J].中国癌症杂志,2005,15(5)：426-428.
[163]Giehl K, Skripczynski B, Mansard A, et al. Growth factor-dependent activation of the Ras-Raf-MEK-MAPK pathway in the human pancreatic carcinoma cell line PANC-1 carrying activated K-ras:implications for cell proliferation and cell migration[J]. Oncogene.2000,19(25):2930-42.
[164]Guo WJ, Zeng MS, Yadav A, et al. Mel-18 acts as a tumor suppressor by repressing Bmi-1 expression and down-regulating AKT activity in breast cancer cells[J]. Cancer Res.2007,67(11): 5083-9.
[165]Lee JY, Jang KS, Shin DH, et al. Mel-18 negatively regulates INK4a/ARF-independent cell cycle progression via AKT inactivation in breast cancer[J]. Cancer Res.2008,68:4201-9.
[166]Gonzalez ME, DuPrie ML, Krueger H, et al. Histone methyltransferase EZH2 induces AKT-dependent genomic instability and BRCA1 inhibition in breast cancer[J]. Cancer Res.71(6): 2360-70.
[167]Hu T, Liu S, Breiter DR, et al. Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis[J]. Cancer Res.2008,68(16):6533-40.
[168]Yoo YA, Kang MH, Lee HJ, et al. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of AKT, EMT, and MMP-9 pathway in gastric cancer[J]. Cancer Res. 71(22):7061-70.
[169]Kubo M, Kuroki S, Tanaka M. New therapeutic target of breast cancer[J]. Nihon Rinsho,2007,65 Suppl 6:142-7.
[170]Zhang LS, Ma HW, Greyner HJ, et al. Inhibition of cell proliferation by CD44:AKT is inactivated and EGR-1 is down-regulated[J]. Cell Prolif,2010,43(4):385-95.
[171]Cha TL, Zhou BP, Xia W, et al. AKT-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3[J]. Science.2005,310(5746):306-10.
[172]Jeong CH, Cho YY, Kim MO, et al. Phosphorylation of Sox2 cooperates in reprogramming to pluripotent stem cells[J]. Stem Cells.28(12):2141-50.
[173]Dubrovska A, Kim S, Salamone RJ, et al. The role of PTEN/AKT/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations[J]. Proc Natl Acad Sci U S A. 2009,106(1):268-73.
[174]Voncken JW, Niessen H, Neufeld B, et al. MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmil[J]. J Biol Chem.2005,280(7):5178-87.
[175]Judd NP, Winkler AE, Murillo-Sauca O, et al. ERK1/2 regulation of CD44 modulates oral cancer aggressiveness[J]. Cancer Res,72(1):365-74.
[176]Mazumdar T, DeVecchio J, Agyeman A, et al. The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer[J]. Oncotarget,2(8):638-45.
[177]Xie J, Aszterbaum M, Zhang X, et al. A role of PDGFRalpha in basal cell carcinoma proliferation[J]. Proc Natl Acad Sci U S A.2001,98(16):9255-9.
[178]Dong L, Qi N, Ge RM, et al. Overexpression of CD133 promotes the phosphorylation of Erk in U87MG human glioblastoma cells[J]. Neurosci Lett,484(3):210-4.
[179]Lee JT Jr, McCubrey JA. The Raf/MEK/ERK signal transduction cascade as a target forchemotherapeutic intervention in leukemia[J]. Leukemia.2002,16(4):486-507.
[180]Wang YK, Zhu YL, Qiu FM, et al. Activation of AKT and MAPK pathways enhances the tumorigenicity of CD133+ primary colon cancer cells[J]. Carcinogenesis,31(8):1376-80.
[181]Leung EL, Fiscus RR, Tung JW, et al. Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties[J]. PLoS One.5(11),2010, e14062.
[182]Su J, Xu XH, Huang Q, et al. Identification of cancer stem-like CD44+ cells in human nasopharyngeal carcinoma cell line[J]. Arch Med Res.2011 Jan,42(1):15-21.
[183]Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells[J]. Genes Dev.2007,21(5): 525-30.
[184]Berezovska OP, Glinskii AB, Yang Z, et al. Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer[J]. Cell Cycle.2006,5(16): 1886-901.
[185]Boyer LA, Lee TI, Cole MF, et al. Core transcriptional regulatory circuitry in human embryonic stem cells[J]. Cell.2005,122(6):947-56.
[186]Dailey L, Basilico C. Coevolution of HMG domains and homeodomains and the generation of transcriptional regulation by Sox/POU complexes[J]. J Cellular Physiol,2001,186(3):315-328
[187]Xiao Y, Ye Y, Yearsley K, et al. The lymphovascular embolus of inflammatory breast cancer expresses a stem cell-like phenotype[J]. Am J Pathol.2008,173(2):561-74.
[1]Al-Agha OM, Nicastri AD. An in-depth look at Krukenberg tumor:an overview[J]. Arch Pathol Lab Med,2006,130(11):1725-30.
[2]Yonemum Y. Bandou E, Kineshita K, et al. Effective therapy for peritoneal dissemination in gastric cancer[J]. Surg Oncol Clin N Am,2003,12:635-648.
[3]Kim HK, Heo DS, Bang YJ. Prognostic factors of Krukenberg's tumor[J]. Gynecol Oncol.2001 Jul, 82(1):105-9.
[4]Cheong JH, Hyung WJ, Chen J, et al. Survival benefit of metastasectomy for Krukenberg tumors from gastric cancer[J]. Gynecol Oncol.2004 Aug,94(2):477-82.
[5]Ayhan A, Guvenal T, Salman MC, et al. The role of cytoreductive surgery in nongenital cancers metastatic to the ovaries[J]. Gynecol Oncol.2005 Aug,98(2):235-41.
[6]McGill F, Ritter DB, Rickard C, et al. Management of Krukenberg tumors:an 11-year experience and review of the literature[J]. Prim Care Update Ob Gyns.1998 Jul 1,5(4):157-158
[7]Cheong JH, Hyung WJ, Chen J, et al. Surgical management and outcome of metachronous Krukenberg tumors from gastric cancer[J], J Surg Oncol.2004 Jul 15,87(1):39-45.
[8]Serov SF, Scully RE. Histologic typing of ovarian tumors. In:International histologic classification of tumors[J]. Geneva:World Health Organization.1973:9,17-8.
[9]Kobayashi O, Sugiyama Y, Cho H, et al. Clinical and pathological study of gastric cancer with ovarian metastasis[J]. Int J Clin Oncol.2003 Apr,8(2):67-71.
[10]McGill FM, Ritter DB, Rickard CS, et al. Krukenberg tumors:can management be improved? [J]. Gynecol Obstet Invest.1999,48(l):61-5.
[11]Duarte I, Llanos O. Patterns of metastases in intestinal and diffuse types of carcinoma of the stomach. Hum Pathol [J].1981 Mar,12(3):237-42.
[12]Wang J, Shi YK, Wu LY, et al. Prognostic factors for ovarian metastases from primary gastric cancer[J]. Int J Gynecol Cancer.2008 Jul-Aug,18(4):825-32.
[13]Yook JH, Oh ST, Kim BS. Clinical prognostic factors for ovarian metastasis in women with gastric cancer[J]. Hepatogastroenterology.2007 Apr-May,54(75):955-9.
[I]Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cellsfJ]. Nature,2001, 414(6859):105-11.
[2]Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells--perspectives on current status and future directions:AACR Workshop on cancer stem cells[J]. Cancer Res,2006,66(19):9339-44.
[3]Bonnet D, Dick JE, et al. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med,1997,3(7):730-7.
[4]Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells[J]. Nature,2004,432(7015):396-401.
[5]Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells[J]. Cancer Res,2005,65(23):10946-51.
[6]Li F, Tiede B, Massague J, et al. Beyond tumorigenesis:cancer stem cells in metastasis[J]. Cell Res, 2007,17(1):3-14.
[7]Welm AL, Kim S, Welm BE, et al. MET and MYC cooperate in mammary tumorigenesis[J]. Proc Natl Acad Sci U S A,2005,102(12):4324-9.
[8]Jaiswal S, Traver D, Miyamoto T, et al. Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias[J]. Proc Natl Acad Sci U S A,2003,100(17):10002-7. Epub 2003 Jul 30.
[9]Bjerkvig R, Tysnes BB, Aboody KS, et al. Opinion:the origin of the cancer stem cell:current controversies and new insights[J]. Nat Rev Cancer,2005,5(11):899-904.
[10]Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells[J]. Oncogene.2004,23(43): 7274-82.
[II]Wright MH, Calcagno AM, Salcido CD, et al. Brcal breast tumors contain distinct CD44+/CD24-and CD133+ cells with cancer stem cell characteristics[J]. Breast Cancer Res,2008;10(l):R10.
[12]Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance[J]. Nat Rev Cancer.2008,8(7):545-54.
[13]Croker AK, Allan AL. Cancer stem cells:implications for the progression and treatment of metastatic disease[J]. J Cell Mol Med,2008,12(2):374-90.
[14]Luzzi KJ, MacDonald IC, Schmidt EE, et al. Multistep nature of metastatic inefficiency:dormancy of solitary cells after successful extravasation and limited survival of early micrometastases[J]. Am J Pathol,1998,153(3):865-73.
[15]Brabletz T, Jung A, Spaderna S, et al. Opinion:migrating cancer stem cells-an integrated concept of malignant tumour progression[J]. Nat Rev Cancer,2005,5(9):744-9.
[16]邓永键等.肿瘤转移干细胞与抗转移策略[J].中国肿瘤生物杂志,2009,16：547-556
[17]Sheridan C, Kishimoto H, Fuchs RK, et al. CD44+/CD24-breast cancer cells exhibit enhanced invasive properties:an early step necessary for metastasis[J]. Breast Cancer Res,2006,8(5):R59.
[18]Pandit TS, Kennette W, Mackenzie L, et al. Lymphatic metastasis of breast cancer cells is associated with differential gene expression profiles that predict cancer stem cell-like properties and the ability to survive, establish and grow in a foreign environment[J]. Int J Oncol,2009,35:297-308
[19]Vincent-Salomon A, Bidard FC, Pierga JY. Bone marrow micrometastasis in breast cancer:review of detection methods, prognostic impact and biological issues[J]. J Clin Pathol,2008,61 (5):570-576.
[20]Balic M, Lin H, Young L, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype[J]. Clin Cancer Res,2006,12 (19):5615-5621.
[21]Yang ZF, Ngai P, Ho DW, et al. Identification of local and circulating cancer stem cells in human liver cancer[J]. Hepatology,2008,47 (3):919-928.
[22]Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease[J]. Cell,2009,139(5):871-90.
[23]Yang J, Weinberg RA. Epithelial-mesenchymal transition:at the crossroads of development and tumor metastasis. Dev Cell[J].2008 Jun;14(6):818-29.
[24]Stover DG, Bierie B, Moses HL. A delicate balance:TGF-beta and the tumor microenvironment[J]. J Cell Biochem,2007,101 (4):851-61.
[25]Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells[J]. Cell,2008,133(4):704-15.
[26]Morel AP, Lievre M, Thomas C, et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition[J]. PLoS One,2008,3(8):e2888.
[27]Raimondi C, Gianni W, Cortesi E, et al. Cancer stem cells and epithelial-mesenchymal transition: revisiting minimal residual disease[J]. Curr Cancer Drug Targets.2010,10(5):496-508.
[28]Lou Y, Preobrazhenska O, auf dem Keller U, et al. Epithelial-mesenchymal transition (EMT) is not sufficient for spontaneous murine breast cancer metastasis[J]. Dev Dyn,2008,237(10):2755-68.
[29]Kucia M, Reca R, Miekus K, et al. Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms:Pivotal role of theSDF-1-CXCR4 axis[J]. Stem Cells,2005,23: 879-894
[30]Gelmini S, Mangoni M, Serio M, et al. The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis[J]. J Endocrinol Invest,2008,31(9):809-19.
[31]Wang L, Wang Z, Yang B, et al. CXCR4 nuclear localization follows binding of its ligand SDF-1 and occurs in metastatic but not primary renal cell carcinoma[J]. Oncol Rep,2009,22(6):1333-9.
[32]Hermann PC, Huber SL, Herrier T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer [J]. Cell Stem Sell,2007,1(3):313-323.
[33]Miki J, Furusato B, Li H, et al. Identification of putative stem cell markers, CD133 and CXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens[J]. Cancer Res,2007,67:3153-3161
[34]Krohn A, Song YH, Muehlberg F, et al. CXCR4 receptor positive spheroid forming cells are responsible for tumor invasion in vitro[J]. Cancer Lett,2009,280(1):65-71.
[35]Li L, Neaves WB. Normal stem cells and cancer stem cells:the niche matters[J]. Cancer Res.2006 May 1;66(9):4553-7.
[36]Chepko G, Slack R, Carbott D, et al. Differential alteration of stem and other cell populations in ducts and lobules of TGF alpha and c-Myc transgenic mouse mammary epithelium[J]. Tissue Cell.2005 Oct;37(5):393-412.
[37]Sneddon JB, Werb Z. Location, location, location:the cancer stem cell niche[J]. Cell Stem Cell, 2007,1:607-611
[38]Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche[J]. Nature,2005,438(7069):820-7.
[39]Buckley CD, Pilling D, Lord JM, et al. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation[J]. Trends Immunol,2001,22(4):199-204.
[2]Yang L. Incidence and mortality of gastric cancer in China[J]. World J Gastroenterol,2006,12(1): 17-20.
[3]Krumlauf R. Hox genes in vertebrate development[J]. Cell,1994,78(2):191-201.
[4]Jacobs JJ, van Lohuizen M. Polycomb repression:from cellular memory to cellular proliferation and cancer[J]. Biochim Biophys Acta,2002,1602(2):151-61.
[5]Takaishi S, Okumura T, Tu S, et al. Identification of gastric cancer stem cells using the cell surface marker CD44[J]. Stem Cells,2009,27(5):1006-20.
[6]Levine SS, King IF, Kingston RE. Division of labor in polycomb group repression[J]. Trends Biochem Sci,2004,29(9):478-85.
[7]Ringrose L, Paro R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins[J]. Annu Rev Genet,2004,38:413-43.
[8]Valk-Lingbeek ME, Bruggeman SW, van Lohuizen M. Stem cells and cancer, the polycomb connection[J]. Cell,2004,118(4):409-18.
[9]Chamberlain SJ, Yee D, Magnuson T. Polycomb repressive complex 2 is dispensable for maintenance of embryonic stem cell pluripotency. Stem Cells,2008,26(6):1496-505.
[10]Pereira CF, Piccolo FM, Tsubouchi T, et al. ESCs require PRC2 to direct the successful reprogramming of differentiated cells toward pluripotency[J]. Cell Stem Cell,2010,6(6):547-56.
[11]Haupt Y, Alexander WS, Barri G, et al. Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E mu-myc transgenic mice[J], Cell,1991,65(5):753-63.
[12]Alkema MJ, Wiegant J, Raap AK, et al. Characterization and chromosomal localization of the human proto-oncogene BMI-1[J]. Hum Mol Genet,1993,2(10):1597-603.
[13]Alkema MJ, Bronk M, Verhoeven E, et al. Identification of Bmil-interacting proteins as constituents of a multimeric mammalian polycomb complex[J]. Genes Dev,1997,11(2):226-40.
[14]van der Lugt NM, Domen J, Linders K, et al. Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene[J]. Genes Dev,1994,8(7):757-69.
[15]Jacobs JJ, Kieboom K, Marino S, et al. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus[J]. Nature,1999,397(6715):164-8.
[16]van Lohuizen M, Frasch M, Wientjens E, et al. Sequence similarity between the mammalian bmi-1 proto-oncogene and the Drosophila regulatory genes Psc and Su(z)2[J]. Nature,1991,353(6342):353-5.
[17]Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells[J]. Nature,2003,423(6937):255-60.
[18]Kim JH, Yoon SY, Kim CN, et al. The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p161NK4a/p14ARF proteins[J]. Cancer Lett,2004,203(2): 217-24.
[19]Dimri GP, Martinez JL, Jacobs JJ, et al. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells[J]. Cancer Res.2002,62(16):4736-45.
[20]Kim JH, Yoon SY, Jeong SH, et al. Overexpression of Bmi-1 oncoprotein correlates with axillary lymph node metastases in invasive ductal breast cancer[J]. Breast,2004,13(5):383-8.
[21]Mihic-Probst D, Kuster A, Kilgus S, et al. Consistent expression of the stem cell renewal factor BMI-1 in primary and metastatic melanoma[J]. Int J Cancer,2007,121(8):1764-70.
[22]黄开红,刘建化,李学先,et al. Bmi-1在胃癌组织中的表达及相关性研究[J].中国肿瘤临床,2007,34(17)：961-965.
[23]Liu JH, Song LB, Zhang X, et al. Bmi-1 expression predicts prognosis for patients with gastric carcinoma[J]. J Surg Oncol,2008,97(3):267-72.
[24]Zhang XW, Sheng YP, Li Q, et al. BMI1 and Mel-18 oppositely regulate carcinogenesis and progression of gastric cancer[J]. Mol Cancer,9:40.
[25]Song LB, Zeng MS, Liao WT, et al. Bmi-1 is a novel molecular marker of nasopharyngeal carcinoma progression and immortalizes primary human nasopharyngeal epithelial cells[J]. Cancer Res, 2006,66(12):6225-32.
[26]Choi YJ, Choi YL, Cho EY, et al. Expression of Bmi-1 protein in tumor tissues is associated with favorable prognosis in breast cancer patients[J]. Breast Cancer Res Treat,2009,113(1):83-93.
[27]Asano H, Ishida A, Hasegawa M, et al. The mouse Mel-18 "RING-finger" gene:genomic organization, promoter analysis and chromosomal assignment[J]. DNA Seq,1993,3(6):369-77.
[28]Goebl MG. The bmi-1 and mel-18 gene products define a new family of DNA-binding proteins involved in cell proliferation and tumorigenesis[J]. Cell,1991,66(4):623.
[29]Akasaka T, Kanno M, Balling R, et al. A role for mel-18, a Polycomb group-related vertebrate gene, during theanteroposterior specification of the axial skeleton[J]. Development,1996,122(5):1513-22.
[30]Elderkin S, Maertens GN, Endoh M, et al. A phosphorylated form of Mel-18 targets the Ring1B histone H2A ubiquitin ligase to chromatin[J]. Mol Cell,2007,28(1):107-20.
[31]Kanno M, Hasegawa M, Ishida A, et al. Mel-18, a Polycomb group-related mammalian gene, encodes a transcriptional negative regulator with tumor suppressive activity[J]. EMBO J,1995,14(22): 5672-8.
[32]Wiederschain D, Chen L, Johnson B, et al. Contribution of polycomb homologues Bmi-1 and Mel-18 to medulloblastoma pathogenesis[J]. Mol Cell Biol,2007,27(13):4968-79.
[33]Guo WJ, Datta S, Band V, Dimri GP. Mel-18, a polycomb group protein, regulates cell proliferation and senescence via transcriptional repression of Bmi-1 and c-Myc oncoproteins[J]. Mol Biol Cell,2007, 18(2):536-46.
[34]Tetsu O, Ishihara H, Kanno R, et al. mel-18 negatively regulates cell cycle progression upon B cell antigen receptor stimulation through a cascade leading to c-myc/cdc25[J]. Immunity,1998,9(4):439-48.
[35]Chun T, Rho SB, Byun HJ, et al. The polycomb group gene product Mel-18 interacts with cyclin D2 and modulates its activity[J]. FEBS Lett,2005,579(24):5275-80.
[36]Guo BH, Zhang X, Zhang HZ, et al. Low expression of Mel-18 predicts poor prognosis in patients with breast cancer. Ann Oncol,2010,21(12):2361-9.
[37]Wang W, Lin T, Huang J, et al. Analysis of Mel-18 expression in prostate cancer tissues and correlation with clinicopathologic features[J]. Urol Oncol,2009,29(3):244-51.
[38]Lu YW, Li J, Guo WJ. Expression and clinicopathological significance of Mel-18 and Bmi-1 mRNA in gastric carcinoma[J]. J Exp Clin Cancer Res,2010,29:143.
[39]Hobert O, Jallal B, Ullrich A. Interaction of Vav with ENX-1 a putative transcriptional regulator of homeobox gene expression [J]. Mol Cell Biol,1996,16(6):3066-3073
[40]Cardoso C, Mignon C, Hetet G, et al. The human EZH2 gene:genomic organisation and revised mapping in 7q35 within the critical region for malignant myeloid disorders[J]. Eur J Hum Genet,2000, 8(3):174-80.
[41]Kondo Y, Shen L, Cheng AS, et al. Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation[J]. Nat Genet,2008,40(6):741-50.
[42]Lee TI, Jenner RG, Boyer LA, et al. Control of developmental regulators by Polycomb in human embryonic stem cells[J]. Cell,2006,125(2):301-13.
[43]Plath K, Fang J, Mlynarczyk-Evans SK, et al. Role of histone H3 lysine 27 methylation in X inactivation[J]. Science,2003,300(5616):131-5.
[44]Caretti G, Di Padova M, Micales B, et al. The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation[J]. Genes Dev,2004,18(21):2627-38.
45 Suva ML, Riggi N, Janiszewska M, et al. EZH2 is essential for glioblastoma cancer stem cell maintenance[J]. Cancer Res,2009,69(24):9211-8.
[46]Chen Y, Lin MC, Yao H, et al. Lentivirns. mediated RNA interference targeting enhancer of zeste homolog 2 inhibits hepatocellular carcinoma growth through down-regulation of stathmin [J]. Hepatology,2007,46(1):200.
[47]Fujii S, Ochiai A. Enhancer of zeste homolog 2 downregulates E-cadherin by mediating histone H3 methylation in gastric cancer cells[J]. Cancer Sci,2008,99(4):738-746.
[48]Wang C, Liu X, Chen Z, et al. Polycomb group protein EZH2-mediated E-cadherin repression promotes metastasis of oral tongue squamous cell carcinoma[J]. Mol Carcinog,2011.
[49]Bracken AP, Pasini D, Capra M, et al. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer[J]. EMBO J,2003,22(20):5323-5335.
[50]Rajasekhar VK, Begemann M. Concise review:roles of polycomb group proteins in development and disease:a stem cell perspective[J]. Stem Cells,2007,25(10):2498-510.
[51]Rao ZY, Cai MY, Yang GF, et al. EZH2 supports ovarian carcinoma cell invasion and/or metastasis via regulation of TGF-betal and is a predictor of outcome in ovarian carcinoma patients[J]. Carcinogenesis.2010,31(9):1576-83.
[52]Matsukawa Y, Semba S, Kato H, et al. Expression of the enhancer of zeste homolog 2 is correlated with poor prognosis in human gastric cancer[J]. Cancer Sci.2006,97(6):484-91.
[53]苗芳,李劲松.EZHZ和Ki-67在胃癌中的表达及其临床意义[J].泰山医学院学报,2008,29(2)：87-89.
[54]Kleer CG, Can Q, Varambal]y S, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells [J]. Proc Nail Acad Sci USA,2003,100(20): 11606-11611.
[55]Mattioli E, Vogiatzi P, Sun A, et al. Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, pl6(INK4A), p27(KIP1), p21(WAF1), Ki-67 expression patterns in gastric cancer[J]. J Cell Physiol. 2007,210(1):183-91.
[56]Sudo T, Utsunomiya T, Mimori K, et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma[J]. Br J Cancer.2005,92(9):1754-8.
[57]Chen Y, Xie D, Yin Li W, et al. RNAi targeting EZH2 inhibits tumor growth and liver metastasis of pancreatic cancer in vivo[J]. Cancer Lett.2010,297(1):109-16.
[58]Fluge, et al. Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis[J]. British Journal of Cancer (2009) 101,1282-1289.
[59]Ciarapica R, Russo G, Verginelli F, et al. Deregulated expression of miR-26a and Ezh2 in rhabdomyosarcoma[J]. Cell Cycle.2009,8(1):172-5.
[60]Mimori K, Ogawa K, Okamoto M, et al. Clinical significance of enhancer of zeste homolog 2 expression in colorectal cancer cases[J]. Eur J Surg Oncol.2005,31(4):376-80.
[61]Gil J, Bernard D, Martinez D, et al. Polycomb CBX7 has a unifying role in cellular lifespan[J]. Nat Cell Biol,2004,6(1):67-72.
[62]Scott CL, Gil J, Hernando E, et al. Role of the chromobox protein CBX7 in lymphomagenesis[J]. Proc Natl Acad Sci U S A.2007,104(13):5389-94.
[63]Zhang XW, Zhang L, Qin W, et al. Oncogenic role of the chromobox protein CBX7 in gastric cancer[J]. J Exp Clin Cancer Res.2010,29:114.
[64]Karamitopoulou E, Pallante P, Zlobec I, et al. Loss of the CBX7 protein expression correlates with a more aggressive phenotype in pancreatic cancer[J]. Eur J Cancer.46(8):1438-44.
[65]管振坡,谷连坤,邢宝才,et al.色素框同源蛋白7基因在人体多种癌组织中表达下调[J].中华预防医学杂志,2011,45(7).
[66]Pallante P, Federico A, Berlingieri MT, et al. Loss of the CBX7 gene expression correlates with a highly malignant phenotype in thyroid cancer[J]. Cancer Res.2008,68(16):6770-6778.
[67]Hinz S, Kempkensteffen C, Christoph F, et al. Expression parameters of the polycomb group proteins BMI1, SUZ12, RING1 and CBX7 in urothelial carcinoma of the bladder and their prognostic relevanceTumor [J]. Biol.2008,29:323-329.
[68]Herr W, Cleary MA. The POU domain:versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain[J]. Genes Dev.1995,9(14):1679-93.
[69]Scholer HR, Balling R, Hatzopoulos AK, et al. Octamer binding proteins confer transcriptional activity in early mouse embryogenesis[J]. EMBO J.1989,8(9):2551-7.
[70]Rodriguez R T, Velkey J M, Lutzko C, et al. Manipulation of Oct4 levels in human embryonic stem cells results in induction of differential cell types [J]. Exp Biol Med,2007,232(10):1368-1380.
[71]Yu J, Vodyanik M A, Smuga-Otto K, et al. Induced pluripotent stem cell lines derived from human somatic cells [J]. Science,2007,318(5858):1917-1920.
[72]Gu P, Le Menuet D, Chung AC, et al. Differential recruitment of methylated CpG binding domains by the orphan receptor GCNF initiates the repression and silencing of Oct4 expression[J]. Mol Cell Biol. 2006,26(24):9471-83.
[73]Melchior K, Weiss J, Zaehres H, et al. The WNT receptor FZD7 contributes self-renewal signaling of human embryonic stem cells [J]. Biol Chem,2008,389(7):897-903.
[74]Liu CG, Lu Y, Wang BB, et al. Clinical implications of stem cell gene Oct-4 expression in breast cancer[J]. Ann Surg.2011,253(6):1165-71.
[75]Chen YC, Hsu HS, Chen YW, et al. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells[J]. PLoS One.2008,3(7):e2637.
[76]Chiou SH, Wang ML, Chou YT, et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation[J]. Cancer Res.2010,70(24):10433-44.
[77]Zito G, Richiusa P, Bommarito A, et al. In vitro identification and characterization of CD133(pos) cancer stem-like cells in anaplastic thyroid carcinoma cell lines[J]. PLoS One.2008,3(10):e3544.
[78]Xu XL, Xing BC, Han HB, et al. The properties of tumor-initiating cells from a hepatocellular carcinoma patient's primary and recurrent tumor[J]. Carcinogenesis.31(2):167-74.
[79]Zhang Y, Peng J, Zhang H, et al. Notch1 signaling is activated in cells expressing embryonic stem cell proteins in human primary nasopharyngeal carcinoma[J]. J Otolaryngol Head Neck Surg.2010, 39(2):157-66.
[80]Yuan F, Zhou W, Zou C, et al. Expression of Oct4 in HCC and modulation to wnt/beta-catenin and TGF-beta signal pathways. Mol Cell Biochem[J].2010,343(1-2):155-62.
[81]Ong CW, Kim LG, Kong HH, et al. CD133 expression predicts for non-response to chemotherapy in colorectal cancer[J]. Mod Pathol.2010,23(3):450-7.
[82]姚宏亮,杨竹林,李永国,et al.胃良恶性病变组织中PSCA和Oct-4的表达及意义[J].中南大学学报(医学版),2008,8.
[83]Chen Z, Xu WR, Qian H, et al. Oct4, a novel marker for human gastric cancer[J].J Surg Oncol. 2009,99(7):414-9.
[84]Sinclair AH, Berta P, Palmer MS, et al. A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif[J]. Nature.1990,346(6281):240-4.
[85]Wegner M. From head to toes:the multiple facets of Sox proteins[J]. Nucleic Acids Res.1999,27(6): 1409-20.
[86]Zhang W, Glockner SC, Guo M, et al. Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer[J]. Cancer Res.2008,68(8):2764-72.
[87]Harley VR, Lovell-Badge R, Goodfellow PN. Definition of a consensus DNA binding site for SRY[J]. Nucleic Acids Res.1994,22(8):1500-1.
[88]Chew JL, Loh YH, Zhang W, et al. Reciprocal transcriptional regulation of Pou5fl and Sox2 via the Oct4/Sox2 complex in embryonic stem cells[J]. Mol Cell Biol.2005,25(14):6031-46.
[89]Chen Y, Shi L, Zhang L, et al. The molecular mechanism governing the oncogenic potential of Sox2 in breast cancer[J]. J Biol Chem.2008,283(26):17969-78.
[90]Ye F, Li Y, Hu Y, et al.. Expression of Sox2 in human ovarian epithelial carcinoma. J Cancer Res Clin Oncol[J].2010,137(1):131-7.
[91]Mutoh H, Sashikawa M, Sugano K. Sox2 expression is maintained while gastric phenotype is completely lost in Cdx2-induced intestinal metaplastic mucosa[J]. Differentiation.2010,81(2):92-8.
[92]Li XL, Eishi Y, Bai YQ, et al. Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma[J]. Int J Oncol,2004.24(2):257-63.
[93]Qi H, Pei D. The magic of four:induction of pluripotent stem cells from somatic cells by Oct4, Sox2, Myc and Klf4[J]. Cell Res.2007,17(7):578-80.
[94]Otsubo T, Akiyama Y, Yanagihara K, et al. Sox2 is frequently downregulated in gastric cancers and inhibits cell growth through cell-cycle arrest and apoptosis[J]. Br J Cancer,2008,98(4):824-831.
[95]Zhang X, Yu H, Yang Y, et al, Sox2 in gastric carcinoma, but not Hathl, is related to patients' clinicopathological features and prognosis[J]. J Gastrointest Surg.2010,14(8):1220-6.
[96]Matsuoka J, Yashiro M, Sakurai K, et al., Role of the Sternness Factors Sox2, Oct3/4, and Nanog in Gastric Carcinoma[J]. J Surg Res,2010.
[97]Kinzler KW, Bigner SH, Bigner DD, et al. Identification of an amplified, highly expressed gene in a human glioma. Science[J].1987,236(4797):70-3.
[98]Karhadkar SS, Bova GS, Abdallah N, et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis[J]. Nature.2004(7009),431:707-12.
[99]Machold R, Hayashi S, Rutlin M, et al. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches[J]. Neuron.2003,39(6):937-50.
[100]Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells[J]. Cancer Res.2006,66(12):6063-71.
[101]Peacock CD, Wang Q, Gesell GS, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma[J]. Proc Natl Acad Sci U S A.2007,104(10):4048-53.
[102]Clement V, Sanchez P, de Tribolet N, et al. HEDGEHOG-Glil signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity[J]. Curr Biol.2007,17(2):165-72.
[103]鲁智豪,贾军,任军,etal.乳腺癌干细胞的检测及Hedgehog信号通路关键分子的表达[J].北京大学学报(医学版),2008,5,480-485.
[104]Song Z, Yue W, Wei B, et al. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer[J]. PLos One,2011,6(3):e17687.
[105]Lupi O. Correlations between the sonic hedgehog pathway and basal cell carcinoma[J]. Int J Dermatol,2007,46(11):1113-7
[106]Sengupta A, Banerjee D, Chandra S, et al. Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression[J]. Leukemia.2007,21 (5):949-55.
[107]Stecca B, Mas C, Clement V, et al. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between Glil and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A[J].2007, 104(14):5895-900.
[108]Dennler S, Andre J, Alexaki I, et al. Induction of sonic hedgehog mediators by transforming growth factor-beta:Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer Res[J]. 2007,67(14):6981-6.
[109]Rao G, Pedone CA, Coffin CM, et al. c-Myc enhances sonic hedgehog-induced medulloblastoma formation from nestin-expressing neural progenitors in mice[J]. Neoplasia.2003,5(3):198-204.
[110]Stecca B, Ruiz i Altaba A. A Glil-p53 inhibitory loop controls neural stem cell and tumour cell numbers[J]. EMBO J.2009,28(6):663-76.
[111]Yoo YA, Kang MH, Kim JS, et al. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway[J]. Carcinogenesis.2008,29(3):480-90.
[112]Das S, Harris LG, Metge BJ, et al. The hedgehog pathway transcription factor Gli1 promotes malignant behavior of cancer cells by up-regulating osteopontin[J]. J Biol Chem.2009,284(34): 22888-97.
[113]Fernandez-Zapico ME. Primers on molecular pathways GLI:more than just Hedgehog? [J] Pancreatology.2008,8(3):227-9.
[114]Ohta M, Tateishi K, Kanai F, et al. p53-Independent negative regulation of p21/cyclin-dependent kinase-interacting protein 1 by the sonic hedgehog-glioma-associated oncogene 1 pathway in gastric carcinoma cells[J]. Cancer Res.2005,65(23):10822-9.
[115]Ma X, Chen K, Huang S, et al. Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas[J]. Carcinogenesis.2005,26(10):1698-705.
[116]Yanai K, Nagai S, Wada J, et al. Hedgehog signaling pathway is a possible therapeutic target for gastric cancer[J]. J Surg Oncol.2007,95(1):55-62.
[117]Chatel G, Ganeff C, Boussif N, et al. Hedgehog signaling pathway is inactive in colorectal cancer cell lines[J]. Int J Cancer.2007,121(12):2622-7.
[118]Feldmann G, Habbe N, Dhara S, et al. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer[J]. Gut.2008,57(10):1420-30.
[119]Choi CH, Roh CR, Kim TJ, et al. Expression of CD44 adhesion molecules on human placentae[J]. Eur J Obstet Gynecol Reprod Biol.2006,128(1-2):243-7.
[120]Honeth G, Bendahl PO, Ringner M, et al. The CD44+/CD24-phenotype is enriched in basal-like breast tumors[J]. Breast Cancer Res.2008,10(3):R53.
[121]Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells [J]. Cancer Res, 2007,67(3):1030-1037.
[122]Pham PY, Phan NL, Nguyen NT, et al. Differentiation of breast cancer stem cells by knockdown of CD44:promising differentiation therapy[J]. J Transl Med.2011,9:209.
[123]Rocco A, Liguori E, Pirozzi G, et al. CD133 and CD44 Cell surface markers do not identify cancer stem cells in primary human gastric tumors[J]. J Cell Physiol.2012,227(6):2686-93.
[124]Lee JL, Wang MJ, Sudhir PR, et al. Osteopontin promotesintegrin activation through outside-in and inside-out mechanism:OPN-CD44v interaction enhances survival in gastrointestinal cancer cells[J]. Cancer Res,2007,67:2089.
[125]Wielenga VJ, Smits R, Korinek V, et al. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway[J]. Am J Pathol,1999,154:515.
[126]Zhu D, Bourguignon LY. Interaction between CD44 and the repeat domain of ankyrin promotes hyaluronic acid-mediated ovarian tumor cell migration[J]. J Cell Physiol,2000,183(2):182-95.
[127]Li CZ, Liu B, Wen ZQ, et al. Inhibition of CD44 expression by small interfering RNA to suppress the growth and metastasis of ovarian cancer cells in vitro and in vivo[J]. Folia Biol (Praha).2008,54(5): 180-6.
[128]Ghaffarzadehgan K, Jafarzadeh M, Raziee HR, et al. Expression of cell adhesion molecule CD44 in gastric adenocarcinoma and its prognostic importance[J]. World J Gastroenterol.2008, 14(41):6376-81.
[129]王庆才,高阳,侯刚,et al.应用组织芯片技术检测胃癌组织中抑癌基因、环氧合酶4和CD44的表达[J].中华消化杂志,2007,4,27(4),280.
[130]Nishii T, Yashiro M, Shinto O, et al. Cancer stem cell-like SP cells have a high adhesion ability to the peritoneum in gastric carcinoma[J]. Cancer Sci,2009,100(8):1397
[131]Heridan C, Kis himot o H, Fuchs RK, et al. CD44+/CD24-breast cancer cells exhibit enhanced in vasive properties:an early step necessary for metastasis [J]. Breast C ancer Res 2006,8(5):R59.
[132]Balic M, Lin H, Young L, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have putative breast cancer stem cell phenotype[J]. Clin Cancer Res,2006, 12(19):5615-5621.
[133]Amirghofran Z, Jalali SA, Hosseini SV, et al. Evaluation of CD44 and CD44v6 in colorectal carcinoma patients:soluble forms in relation to tumor tissue expression and metastasis[J]. J Gastrointest Cancer.2008,39(1-4):73-8.
[134]Kunimura T, Yoshida T, Sugiyama T, et al. The Relationships Between Loss of Standard CD44 Expression and Lymph Node, Liver Metastasis in T3 Colorectal Carcinoma[J]. J Gastrointest Cancer. 2009,40(3-4):115-8.
[135]ISongun, SV Litvinov, CJH van de Velde, et al. Loss of Ep-CAM(CO17-1A) expression predicts survival in patients with gastric cancer[J]. British Journal of Cancer,2005,92(9):1767.
[136]Yin AH, Miraglia S, Zanjani ED, et al. AC 133, a novel marker for human hematopoietic stem and progenitor cells[J]. Blood.1997,90(12):5002-12.
[137]Gordon PR, Leimig T, Babarin-Dorner A, et al. Large-scale isolation of CD133+ progenitor cells from G-CSF mobilized peripheral blood stem cells[J]. Bone Marrow Transplant.2003,31(1):17-22.
[138]Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells[J]. Nature.2004,432(7015):396-401.
[139]Liu G, Yuan X, Zeng Z, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma[J]. Mol Cancer.2006,5(5):67.
[140]O'Brien CA, Pollett A, Gallinger S, et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice[J]. Nature.2007,445(7123):106-10.
[141]Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer[J]. Cell Stem Cell.2007,1(3):313-23.
[142]Smith LM, Nesterova A, Ryan MC, et al. CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers[J]. Br J Cancer.2008,99(1):100-9.
[143]Karbanova J, Missol-Kolka E, Fonseca AV, et al. The stem cell marker CD 133 (Prominin-1) is expressed in various human glandular epithelia[J]. J Histochem Cytochem.2008,56(11):977-93.
[144]Ulasov Ⅳ, Nandi S, Dey M, et al. Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+)glioma stem cells to temozolomide therapy[J]. Mol Med.2010,17(1-2):103-12.
[145]Deng YH, Pu XX, Huang MJ, et al.5-Fluorouracil upregulates the activity of Wnt signaling pathway in CD133-positive colon cancer stem-like cells[J]. Chin J Cancer.2010,29(9):810-5.
[146]唐毕峰,马立业,瞿羽佳,et al.肿瘤干细胞标志物CD133在胃癌中的表达及其临床意义[J].临床肿瘤学杂志,2008,13(6)：495-498.
[147]Ishigami S, Ueno S, Arigami T, et al. Prognostic impact of CD133 expression in gastric carcinoma. Anticancer Res[J].2010,30(6):2453-7.
[148]Wakamatsu Y, Sakamoto N, Oo HZ, et al. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer[J]. Pathol Int.2012,62(2): 112-9.
[149]Mehra N, Penning M, Maas J, et al. Progenitor marker CD 133 mRNA is elevated in peripheral blood of cancer patients with bone metastases[J]. Clin Cancer Res.2006,12(16):4859-66.
[150]Huang X, Sheng Y, Guan M. Co-expression of stem cell genes CD 133 and CD44 in colorectal cancers with early liver metastasis[J]. Surg Oncol,2011.
[151]Boegl M, Prinz C. CD133 expression in different stages of gastric adenocarcinoma[J]. Br J Cancer. 2009,100(8):1365-6, author reply 7.
[152]Lee SH, Kim HS, Park WS, et al. Non-small cell lung cancers frequently express phosphorylated AKT, an immunohistochemical study[J].2002,110(7-8):587-92.
[153]Mayo LD, Donner DB. A phosphatidylinositol 3-kinase/AKT pathway promotestranslocation of Mdm2 from the cytoplasm to the nucleus[J]. Proc Natl Acad Sci U S A.2001,98(20):11598-603.
[154]Grille SJ, Bellacosa A, Upson J, et al. The protein kinase AKT induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines[J]. Cancer Res.2003,63(9):2172-8.
[155]Tazzari PL, Cappellini A, Ricci F, et al. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/AKT signal transduction network in human acute myelogenous leukemia blasts[J]. Leukemia.2007,21(3):427-38.
[156]Cinti C, Vindigni C, Zamparelli A, et al. Activated AKT as an indicator of prognosis in gastric cancer[J]. Virchows Arch.2008,453(5):449-55.
[157]Nam SY, Lee HS, Jung GA, et al. AKT/PKB activation in gastric carcinomas correlates with clinicopathologic variables and prognosis[J]. APMIS.2003,111(12):1105-13.
[158]David O, Jett J, LeBeau H, et al. Phospho-AKT overexpression in non-small cell lung cancer confers significant stage-independent survival disadvantage[J]. Clin Cancer Res.2004,10(20):6865-71.
[159]Massion PP, Taflan PM, Shyr Y, et al. Early involvement of the phosphatidylinositol 3-kinase/AKT pathway in lung cancer progression[J]. Am J Respir Crit Care Med.2004,170(10):1088-94.
[160]Li J, Wang G, Wang C, et al. MEK/ERK signaling contributes to the maintenance of human embryonic stem cell self-renewal [J]. Differentiation.2007,75(4):299-307.
[161]许春进,陈玉龙,韩敏,et al.转化生长因子β1和磷酸化细胞外信号调节激酶在胃癌中的表达[J].中华内科杂志,2006,45(7),586-7.
[162]董慧明,刘刚,吴炅,et al. MAPK信号传导通路对人炎性乳腺癌细胞系侵袭能力的影响[J].中国癌症杂志,2005,15(5)：426-428.
[163]Giehl K, Skripczynski B, Mansard A, et al. Growth factor-dependent activation of the Ras-Raf-MEK-MAPK pathway in the human pancreatic carcinoma cell line PANC-1 carrying activated K-ras:implications for cell proliferation and cell migration[J]. Oncogene.2000,19(25):2930-42.
[164]Guo WJ, Zeng MS, Yadav A, et al. Mel-18 acts as a tumor suppressor by repressing Bmi-1 expression and down-regulating AKT activity in breast cancer cells[J]. Cancer Res.2007,67(11): 5083-9.
[165]Lee JY, Jang KS, Shin DH, et al. Mel-18 negatively regulates INK4a/ARF-independent cell cycle progression via AKT inactivation in breast cancer[J]. Cancer Res.2008,68:4201-9.
[166]Gonzalez ME, DuPrie ML, Krueger H, et al. Histone methyltransferase EZH2 induces AKT-dependent genomic instability and BRCA1 inhibition in breast cancer[J]. Cancer Res.71(6): 2360-70.
[167]Hu T, Liu S, Breiter DR, et al. Octamer 4 small interfering RNA results in cancer stem cell-like cell apoptosis[J]. Cancer Res.2008,68(16):6533-40.
[168]Yoo YA, Kang MH, Lee HJ, et al. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of AKT, EMT, and MMP-9 pathway in gastric cancer[J]. Cancer Res. 71(22):7061-70.
[169]Kubo M, Kuroki S, Tanaka M. New therapeutic target of breast cancer[J]. Nihon Rinsho,2007,65 Suppl 6:142-7.
[170]Zhang LS, Ma HW, Greyner HJ, et al. Inhibition of cell proliferation by CD44:AKT is inactivated and EGR-1 is down-regulated[J]. Cell Prolif,2010,43(4):385-95.
[171]Cha TL, Zhou BP, Xia W, et al. AKT-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3[J]. Science.2005,310(5746):306-10.
[172]Jeong CH, Cho YY, Kim MO, et al. Phosphorylation of Sox2 cooperates in reprogramming to pluripotent stem cells[J]. Stem Cells.28(12):2141-50.
[173]Dubrovska A, Kim S, Salamone RJ, et al. The role of PTEN/AKT/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations[J]. Proc Natl Acad Sci U S A. 2009,106(1):268-73.
[174]Voncken JW, Niessen H, Neufeld B, et al. MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmil[J]. J Biol Chem.2005,280(7):5178-87.
[175]Judd NP, Winkler AE, Murillo-Sauca O, et al. ERK1/2 regulation of CD44 modulates oral cancer aggressiveness[J]. Cancer Res,72(1):365-74.
[176]Mazumdar T, DeVecchio J, Agyeman A, et al. The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer[J]. Oncotarget,2(8):638-45.
[177]Xie J, Aszterbaum M, Zhang X, et al. A role of PDGFRalpha in basal cell carcinoma proliferation[J]. Proc Natl Acad Sci U S A.2001,98(16):9255-9.
[178]Dong L, Qi N, Ge RM, et al. Overexpression of CD133 promotes the phosphorylation of Erk in U87MG human glioblastoma cells[J]. Neurosci Lett,484(3):210-4.
[179]Lee JT Jr, McCubrey JA. The Raf/MEK/ERK signal transduction cascade as a target forchemotherapeutic intervention in leukemia[J]. Leukemia.2002,16(4):486-507.
[180]Wang YK, Zhu YL, Qiu FM, et al. Activation of AKT and MAPK pathways enhances the tumorigenicity of CD133+ primary colon cancer cells[J]. Carcinogenesis,31(8):1376-80.
[181]Leung EL, Fiscus RR, Tung JW, et al. Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties[J]. PLoS One.5(11),2010, e14062.
[182]Su J, Xu XH, Huang Q, et al. Identification of cancer stem-like CD44+ cells in human nasopharyngeal carcinoma cell line[J]. Arch Med Res.2011 Jan,42(1):15-21.
[183]Bracken AP, Kleine-Kohlbrecher D, Dietrich N, et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells[J]. Genes Dev.2007,21(5): 525-30.
[184]Berezovska OP, Glinskii AB, Yang Z, et al. Essential role for activation of the Polycomb group (PcG) protein chromatin silencing pathway in metastatic prostate cancer[J]. Cell Cycle.2006,5(16): 1886-901.
[185]Boyer LA, Lee TI, Cole MF, et al. Core transcriptional regulatory circuitry in human embryonic stem cells[J]. Cell.2005,122(6):947-56.
[186]Dailey L, Basilico C. Coevolution of HMG domains and homeodomains and the generation of transcriptional regulation by Sox/POU complexes[J]. J Cellular Physiol,2001,186(3):315-328
[187]Xiao Y, Ye Y, Yearsley K, et al. The lymphovascular embolus of inflammatory breast cancer expresses a stem cell-like phenotype[J]. Am J Pathol.2008,173(2):561-74.
[1]Al-Agha OM, Nicastri AD. An in-depth look at Krukenberg tumor:an overview[J]. Arch Pathol Lab Med,2006,130(11):1725-30.
[2]Yonemum Y. Bandou E, Kineshita K, et al. Effective therapy for peritoneal dissemination in gastric cancer[J]. Surg Oncol Clin N Am,2003,12:635-648.
[3]Kim HK, Heo DS, Bang YJ. Prognostic factors of Krukenberg's tumor[J]. Gynecol Oncol.2001 Jul, 82(1):105-9.
[4]Cheong JH, Hyung WJ, Chen J, et al. Survival benefit of metastasectomy for Krukenberg tumors from gastric cancer[J]. Gynecol Oncol.2004 Aug,94(2):477-82.
[5]Ayhan A, Guvenal T, Salman MC, et al. The role of cytoreductive surgery in nongenital cancers metastatic to the ovaries[J]. Gynecol Oncol.2005 Aug,98(2):235-41.
[6]McGill F, Ritter DB, Rickard C, et al. Management of Krukenberg tumors:an 11-year experience and review of the literature[J]. Prim Care Update Ob Gyns.1998 Jul 1,5(4):157-158
[7]Cheong JH, Hyung WJ, Chen J, et al. Surgical management and outcome of metachronous Krukenberg tumors from gastric cancer[J], J Surg Oncol.2004 Jul 15,87(1):39-45.
[8]Serov SF, Scully RE. Histologic typing of ovarian tumors. In:International histologic classification of tumors[J]. Geneva:World Health Organization.1973:9,17-8.
[9]Kobayashi O, Sugiyama Y, Cho H, et al. Clinical and pathological study of gastric cancer with ovarian metastasis[J]. Int J Clin Oncol.2003 Apr,8(2):67-71.
[10]McGill FM, Ritter DB, Rickard CS, et al. Krukenberg tumors:can management be improved? [J]. Gynecol Obstet Invest.1999,48(l):61-5.
[11]Duarte I, Llanos O. Patterns of metastases in intestinal and diffuse types of carcinoma of the stomach. Hum Pathol [J].1981 Mar,12(3):237-42.
[12]Wang J, Shi YK, Wu LY, et al. Prognostic factors for ovarian metastases from primary gastric cancer[J]. Int J Gynecol Cancer.2008 Jul-Aug,18(4):825-32.
[13]Yook JH, Oh ST, Kim BS. Clinical prognostic factors for ovarian metastasis in women with gastric cancer[J]. Hepatogastroenterology.2007 Apr-May,54(75):955-9.
[I]Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cellsfJ]. Nature,2001, 414(6859):105-11.
[2]Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells--perspectives on current status and future directions:AACR Workshop on cancer stem cells[J]. Cancer Res,2006,66(19):9339-44.
[3]Bonnet D, Dick JE, et al. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell[J]. Nat Med,1997,3(7):730-7.
[4]Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells[J]. Nature,2004,432(7015):396-401.
[5]Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells[J]. Cancer Res,2005,65(23):10946-51.
[6]Li F, Tiede B, Massague J, et al. Beyond tumorigenesis:cancer stem cells in metastasis[J]. Cell Res, 2007,17(1):3-14.
[7]Welm AL, Kim S, Welm BE, et al. MET and MYC cooperate in mammary tumorigenesis[J]. Proc Natl Acad Sci U S A,2005,102(12):4324-9.
[8]Jaiswal S, Traver D, Miyamoto T, et al. Expression of BCR/ABL and BCL-2 in myeloid progenitors leads to myeloid leukemias[J]. Proc Natl Acad Sci U S A,2003,100(17):10002-7. Epub 2003 Jul 30.
[9]Bjerkvig R, Tysnes BB, Aboody KS, et al. Opinion:the origin of the cancer stem cell:current controversies and new insights[J]. Nat Rev Cancer,2005,5(11):899-904.
[10]Al-Hajj M, Clarke MF. Self-renewal and solid tumor stem cells[J]. Oncogene.2004,23(43): 7274-82.
[II]Wright MH, Calcagno AM, Salcido CD, et al. Brcal breast tumors contain distinct CD44+/CD24-and CD133+ cells with cancer stem cell characteristics[J]. Breast Cancer Res,2008;10(l):R10.
[12]Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance[J]. Nat Rev Cancer.2008,8(7):545-54.
[13]Croker AK, Allan AL. Cancer stem cells:implications for the progression and treatment of metastatic disease[J]. J Cell Mol Med,2008,12(2):374-90.
[14]Luzzi KJ, MacDonald IC, Schmidt EE, et al. Multistep nature of metastatic inefficiency:dormancy of solitary cells after successful extravasation and limited survival of early micrometastases[J]. Am J Pathol,1998,153(3):865-73.
[15]Brabletz T, Jung A, Spaderna S, et al. Opinion:migrating cancer stem cells-an integrated concept of malignant tumour progression[J]. Nat Rev Cancer,2005,5(9):744-9.
[16]邓永键等.肿瘤转移干细胞与抗转移策略[J].中国肿瘤生物杂志,2009,16：547-556
[17]Sheridan C, Kishimoto H, Fuchs RK, et al. CD44+/CD24-breast cancer cells exhibit enhanced invasive properties:an early step necessary for metastasis[J]. Breast Cancer Res,2006,8(5):R59.
[18]Pandit TS, Kennette W, Mackenzie L, et al. Lymphatic metastasis of breast cancer cells is associated with differential gene expression profiles that predict cancer stem cell-like properties and the ability to survive, establish and grow in a foreign environment[J]. Int J Oncol,2009,35:297-308
[19]Vincent-Salomon A, Bidard FC, Pierga JY. Bone marrow micrometastasis in breast cancer:review of detection methods, prognostic impact and biological issues[J]. J Clin Pathol,2008,61 (5):570-576.
[20]Balic M, Lin H, Young L, et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype[J]. Clin Cancer Res,2006,12 (19):5615-5621.
[21]Yang ZF, Ngai P, Ho DW, et al. Identification of local and circulating cancer stem cells in human liver cancer[J]. Hepatology,2008,47 (3):919-928.
[22]Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease[J]. Cell,2009,139(5):871-90.
[23]Yang J, Weinberg RA. Epithelial-mesenchymal transition:at the crossroads of development and tumor metastasis. Dev Cell[J].2008 Jun;14(6):818-29.
[24]Stover DG, Bierie B, Moses HL. A delicate balance:TGF-beta and the tumor microenvironment[J]. J Cell Biochem,2007,101 (4):851-61.
[25]Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells[J]. Cell,2008,133(4):704-15.
[26]Morel AP, Lievre M, Thomas C, et al. Generation of breast cancer stem cells through epithelial-mesenchymal transition[J]. PLoS One,2008,3(8):e2888.
[27]Raimondi C, Gianni W, Cortesi E, et al. Cancer stem cells and epithelial-mesenchymal transition: revisiting minimal residual disease[J]. Curr Cancer Drug Targets.2010,10(5):496-508.
[28]Lou Y, Preobrazhenska O, auf dem Keller U, et al. Epithelial-mesenchymal transition (EMT) is not sufficient for spontaneous murine breast cancer metastasis[J]. Dev Dyn,2008,237(10):2755-68.
[29]Kucia M, Reca R, Miekus K, et al. Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms:Pivotal role of theSDF-1-CXCR4 axis[J]. Stem Cells,2005,23: 879-894
[30]Gelmini S, Mangoni M, Serio M, et al. The critical role of SDF-1/CXCR4 axis in cancer and cancer stem cells metastasis[J]. J Endocrinol Invest,2008,31(9):809-19.
[31]Wang L, Wang Z, Yang B, et al. CXCR4 nuclear localization follows binding of its ligand SDF-1 and occurs in metastatic but not primary renal cell carcinoma[J]. Oncol Rep,2009,22(6):1333-9.
[32]Hermann PC, Huber SL, Herrier T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer [J]. Cell Stem Sell,2007,1(3):313-323.
[33]Miki J, Furusato B, Li H, et al. Identification of putative stem cell markers, CD133 and CXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens[J]. Cancer Res,2007,67:3153-3161
[34]Krohn A, Song YH, Muehlberg F, et al. CXCR4 receptor positive spheroid forming cells are responsible for tumor invasion in vitro[J]. Cancer Lett,2009,280(1):65-71.
[35]Li L, Neaves WB. Normal stem cells and cancer stem cells:the niche matters[J]. Cancer Res.2006 May 1;66(9):4553-7.
[36]Chepko G, Slack R, Carbott D, et al. Differential alteration of stem and other cell populations in ducts and lobules of TGF alpha and c-Myc transgenic mouse mammary epithelium[J]. Tissue Cell.2005 Oct;37(5):393-412.
[37]Sneddon JB, Werb Z. Location, location, location:the cancer stem cell niche[J]. Cell Stem Cell, 2007,1:607-611
[38]Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche[J]. Nature,2005,438(7069):820-7.
[39]Buckley CD, Pilling D, Lord JM, et al. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation[J]. Trends Immunol,2001,22(4):199-204.