胃癌组织中PCNA、Ki-67、Nanog、Oct-4的表达与复发转移的关系
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摘要
背景与目的
胃癌具有恶性程度高、侵袭性强、易耐药的特点,是常见的消化系统肿瘤之一。近年来,肿瘤干细胞理论的发展为恶性肿瘤的治疗带来新的思路。但是,目前胃癌干细胞方面的相关研究还十分有限。基础研究表明,Nanog、Oct-4这些胚胎干细胞的标志物可以作为肿瘤干细胞的标志物,其表达程度与肿瘤的发生、增殖、转移有着密切的关系,但是其表达情况同胃癌患者的预后关系目前还缺乏相关研究。PCNA、Ki-67是常见的恶性肿瘤增殖相关标志物,但是其表达情况与胃癌生存预后和肿瘤干细胞标志物表达之间的联系尚不明确。本研究通过检测干细胞标志物Nanog、Oct-4与增殖相关标志物PCNA、Ki-67在胃癌组织中的表达情况,探讨其表达与病理分期、侵润深度、淋巴结转移等临床病理相关因素,以及无病生存时间(DFS)、转移部位等的相关性。进一步对Nanog、 Oct-4与PCNA、Ki-67的内在联系进行初步探索,为预测胃癌患者术后复发转移风险提供参考。
材料和方法
回顾性分析2007年1月至2008年1月在河南省肿瘤医院行胃癌根治术并术后辅助化疗的69例患者。采用免疫组织化学Elivison方法检测癌组织中Nanog、Oct-4、PCNA、Ki-67的表达情况。运用医学统计软件SPSS10.0进行数据分析,用x2检验或校正后的x2检验分析比较Nanog、Oct-4、PCNA、 Ki-67蛋白在胃癌中的表达与临床病理特征的相关性,以及与无病生存时间及复发转移的关系,采用Kaplan-Meier方法计算生存率并应用Log-rank检验行单因素预后分析,采用Cox回归风险模型行多因素分析,各项标志物之间的相关性应用Sperman分析。
结果
Nanog、Oct-4、PCNA、Ki-67在胃癌组织中的表达率分别为：24.6%,52.2%,52.2%,37.7%。单一指标分析中,临床病理因素方面,Oct-4与分化程度负相关(p=0.041,χ2=4.182);PCNA不同表达组T分期之间的差异则具有统计学意义(p=0.005,χ2=7.951)。DFS方面,Oct-4、PCNA各指标的表达与DFS之间均呈负相关(p分别为0.043,0.032,χ2分别为4.083,4.619)；Nanog、Ki-67不同表达组DFS差异虽然无统计学意义,但阳性表达组DFS有降低的趋势。四项指标复发转移率之间的关系虽无统计学意义,但表达率高的患者其转移复发率有升高的趋势。分组分析中,Nanog,Oct-4三个表达组分化程度差异具有统计学意义(p=0.027,χ2=7.234),DFS之间的差异不具有统计学意义(p=0.053)。PCNA、Ki-67不同表达组在T分期之间的差异则具有统计学意义(p=0.018,χ2=8.016)；全阳性表达组DFS明显低于含任一指标阴性表达的两组(p=0.017,χ2=8.167)。联合分析四项指标发现,表达指标越多DFS是越短的,各组差异具有统计学意义(p=0.028,χ2=10.882)。多因素分析发现,T分期、淋巴结转移情况和Nanog表达情况为DFS独立的危险因素(p均<0.05)。相关性分析中,Nanog与Oct-4、PCNA表达呈正相关,PCNA与Ki-67呈正相关性(p均<0.05)。
结论
Nanog, Oct-4、PCNA、Ki-67独立或联合检测可能成为作为判断术后DFS的预测指标,且表达指标越多可能意味着越差的DFS,联合检测可能更利于判断预后。PCNA单独或与Ki-67联合检测可能与胃癌的浸润能力相关,可能是胃癌早期判断增殖侵袭能力的指标。相关性分析提示Nanog与Oct-4、Nanog与PCNA、PCNA与Ki-67之间可能存在相互作用或调节的通路,与肿瘤的发生和发展密切相关。
Background and Purpose
Gastric cancer is one of the most common malignancies with the characteristics of high malignancy, strong invasiveness and drug resistance. In recent years, the developments of cancer stem cell theories have taken new ideas for the treatment of malignant tumors. However, limited researches have been done in the field of gastric cancer. Markers of embryonic stem cell, such as Nanog, Oct-4are also expressed in cancer stem cells and their expression levels have close correlation with the cancer formation, reproduction and transference. But the relationship between the prognosis of gastric cancer and the expression levels of Nanog and Oct-4is not clear. PCNA and Ki-67are common reproduction biomarkers in malignant tumor. But, the relationship between the expression of PCNA, Ki-67and the prognosis of gastric cancer is unclear. And this research examined the expression of stem cell markers of Nanog, Oct-4and proliferative markers of PCNA and Ki-67in gastric cancer tissues in order to explore the relevance of their expressions and clinical pathology factors such as pathological stage, invasion, and lymphatic metastasisand disease-free survives metastatic sites.The internal relations between Nanog, Oct-4and PCNA, Ki-67are also preliminarily explored.in order to provide some clinical basis for the diagnosis and prognosis of gastric cancer.
Materials and Methods
Sixty-nine patients with gastric cancer from January1,2007, through January1,2008were included in the retrospective study. All these patients had accepted adjunctive chemotherapy followed by surgery. The protein expression levels of Nanog, Oct-4, PCNA and Ki-67were detected by the Elivison immunohistochemistry method. The differences of Nanog, Oct-4, PCNA and Ki-67protein expression levels in gastric cancer tissue were evaluated by Chi-square test or Chi-square test after correction. Kaplan-Meier method was used for analysis of overall survival. The Log-rank test was used for univariate prognostic analysis and Cox proportional hazards regression analyses was used for multivariable prognostic analysis, then use Sperman analyze therelationship between these markers.
Result
Expression rates in gastric cancer of Nanog, Oct-4, PCNA, Ki-67were24.6%,52.2%,52.2%and37.7%. Analysis of a single marker, Clinicopathological factors: Oct-4negatively correlated with the degree of differentiation (p=0.041,x2=4.182). Between the different PCNA expression group, the T stage was statistically significant difference (p=0.005,x2=7.951). Between indicators of PCNA, Oct-4expression and DFS showed a negative correlation (p values were0.043and0.032, respectively,x2values were4.083and4.619, respectively). In different Nanog and Ki-67expression group, the difference of DFS was not statistically significance, but the positive expression group had a lower DFS. Although there was no statistically significant relationship between the recurrence rate and these markers, but the patient with positive expression may have higher metastasis and recurrence rate. Packet analysis:The degree of differentiation in Nanog and Oct-4positive expression group was higher than the other groups (p=0.027,x2=7.234), but the analyze of DFS had no statistically significant difference. PCNA, Ki-67both positive group had lower DFS than the other groups (p=0.017,x2=8.167), and compared with T stage in positive expression group, negative expression group was earlier (p=0.018,x2=8.016). Joint analysis of the four indicators found it was shorter that the DFS in the more indicator expression groups (p=0.028,x2=10.882).Multivariate analysis found that T stage, lymph node metastasis and Nanog expression were independent risk factor for DFS (p<0.05). Correlation analysis, Nanog was positive correlation with Oct-4and PCNA. PCNA and Ki-67was positive relevant too.(p<0.05).
Conclusion
Nanog, Oct-4, PCNA, Ki-67independent or combined detection may become a judgment postoperative DFS predictor, and the more the expression of indicators may mean that the worse DFS. The combined detection may be more conducive to prognosis. PCNA alone or joint with Ki-67detection may related to the ability of tumor invasion,these markers may be indicators of proliferation and invasion capacity in early gastric cancer. Correlation analysis indicate that there may be a relationship between Nanog and Oct-4; Naong and PCNA; PCNA and Ki-67, and may closely related to the occurrence and development of tumors.
胃癌具有恶性程度高、侵袭性强、易耐药的特点,是常见的消化系统肿瘤之一。近年来,肿瘤干细胞理论的发展为恶性肿瘤的治疗带来新的思路。但是,目前胃癌干细胞方面的相关研究还十分有限。基础研究表明,Nanog、Oct-4这些胚胎干细胞的标志物可以作为肿瘤干细胞的标志物,其表达程度与肿瘤的发生、增殖、转移有着密切的关系,但是其表达情况同胃癌患者的预后关系目前还缺乏相关研究。PCNA、Ki-67是常见的恶性肿瘤增殖相关标志物,但是其表达情况与胃癌生存预后和肿瘤干细胞标志物表达之间的联系尚不明确。本研究通过检测干细胞标志物Nanog、Oct-4与增殖相关标志物PCNA、Ki-67在胃癌组织中的表达情况,探讨其表达与病理分期、侵润深度、淋巴结转移等临床病理相关因素,以及无病生存时间(DFS)、转移部位等的相关性。进一步对Nanog、 Oct-4与PCNA、Ki-67的内在联系进行初步探索,为预测胃癌患者术后复发转移风险提供参考。
材料和方法
回顾性分析2007年1月至2008年1月在河南省肿瘤医院行胃癌根治术并术后辅助化疗的69例患者。采用免疫组织化学Elivison方法检测癌组织中Nanog、Oct-4、PCNA、Ki-67的表达情况。运用医学统计软件SPSS10.0进行数据分析,用x2检验或校正后的x2检验分析比较Nanog、Oct-4、PCNA、 Ki-67蛋白在胃癌中的表达与临床病理特征的相关性,以及与无病生存时间及复发转移的关系,采用Kaplan-Meier方法计算生存率并应用Log-rank检验行单因素预后分析,采用Cox回归风险模型行多因素分析,各项标志物之间的相关性应用Sperman分析。
结果
Nanog、Oct-4、PCNA、Ki-67在胃癌组织中的表达率分别为：24.6%,52.2%,52.2%,37.7%。单一指标分析中,临床病理因素方面,Oct-4与分化程度负相关(p=0.041,χ2=4.182);PCNA不同表达组T分期之间的差异则具有统计学意义(p=0.005,χ2=7.951)。DFS方面,Oct-4、PCNA各指标的表达与DFS之间均呈负相关(p分别为0.043,0.032,χ2分别为4.083,4.619)；Nanog、Ki-67不同表达组DFS差异虽然无统计学意义,但阳性表达组DFS有降低的趋势。四项指标复发转移率之间的关系虽无统计学意义,但表达率高的患者其转移复发率有升高的趋势。分组分析中,Nanog,Oct-4三个表达组分化程度差异具有统计学意义(p=0.027,χ2=7.234),DFS之间的差异不具有统计学意义(p=0.053)。PCNA、Ki-67不同表达组在T分期之间的差异则具有统计学意义(p=0.018,χ2=8.016)；全阳性表达组DFS明显低于含任一指标阴性表达的两组(p=0.017,χ2=8.167)。联合分析四项指标发现,表达指标越多DFS是越短的,各组差异具有统计学意义(p=0.028,χ2=10.882)。多因素分析发现,T分期、淋巴结转移情况和Nanog表达情况为DFS独立的危险因素(p均<0.05)。相关性分析中,Nanog与Oct-4、PCNA表达呈正相关,PCNA与Ki-67呈正相关性(p均<0.05)。
结论
Nanog, Oct-4、PCNA、Ki-67独立或联合检测可能成为作为判断术后DFS的预测指标,且表达指标越多可能意味着越差的DFS,联合检测可能更利于判断预后。PCNA单独或与Ki-67联合检测可能与胃癌的浸润能力相关,可能是胃癌早期判断增殖侵袭能力的指标。相关性分析提示Nanog与Oct-4、Nanog与PCNA、PCNA与Ki-67之间可能存在相互作用或调节的通路,与肿瘤的发生和发展密切相关。
Background and Purpose
Gastric cancer is one of the most common malignancies with the characteristics of high malignancy, strong invasiveness and drug resistance. In recent years, the developments of cancer stem cell theories have taken new ideas for the treatment of malignant tumors. However, limited researches have been done in the field of gastric cancer. Markers of embryonic stem cell, such as Nanog, Oct-4are also expressed in cancer stem cells and their expression levels have close correlation with the cancer formation, reproduction and transference. But the relationship between the prognosis of gastric cancer and the expression levels of Nanog and Oct-4is not clear. PCNA and Ki-67are common reproduction biomarkers in malignant tumor. But, the relationship between the expression of PCNA, Ki-67and the prognosis of gastric cancer is unclear. And this research examined the expression of stem cell markers of Nanog, Oct-4and proliferative markers of PCNA and Ki-67in gastric cancer tissues in order to explore the relevance of their expressions and clinical pathology factors such as pathological stage, invasion, and lymphatic metastasisand disease-free survives metastatic sites.The internal relations between Nanog, Oct-4and PCNA, Ki-67are also preliminarily explored.in order to provide some clinical basis for the diagnosis and prognosis of gastric cancer.
Materials and Methods
Sixty-nine patients with gastric cancer from January1,2007, through January1,2008were included in the retrospective study. All these patients had accepted adjunctive chemotherapy followed by surgery. The protein expression levels of Nanog, Oct-4, PCNA and Ki-67were detected by the Elivison immunohistochemistry method. The differences of Nanog, Oct-4, PCNA and Ki-67protein expression levels in gastric cancer tissue were evaluated by Chi-square test or Chi-square test after correction. Kaplan-Meier method was used for analysis of overall survival. The Log-rank test was used for univariate prognostic analysis and Cox proportional hazards regression analyses was used for multivariable prognostic analysis, then use Sperman analyze therelationship between these markers.
Result
Expression rates in gastric cancer of Nanog, Oct-4, PCNA, Ki-67were24.6%,52.2%,52.2%and37.7%. Analysis of a single marker, Clinicopathological factors: Oct-4negatively correlated with the degree of differentiation (p=0.041,x2=4.182). Between the different PCNA expression group, the T stage was statistically significant difference (p=0.005,x2=7.951). Between indicators of PCNA, Oct-4expression and DFS showed a negative correlation (p values were0.043and0.032, respectively,x2values were4.083and4.619, respectively). In different Nanog and Ki-67expression group, the difference of DFS was not statistically significance, but the positive expression group had a lower DFS. Although there was no statistically significant relationship between the recurrence rate and these markers, but the patient with positive expression may have higher metastasis and recurrence rate. Packet analysis:The degree of differentiation in Nanog and Oct-4positive expression group was higher than the other groups (p=0.027,x2=7.234), but the analyze of DFS had no statistically significant difference. PCNA, Ki-67both positive group had lower DFS than the other groups (p=0.017,x2=8.167), and compared with T stage in positive expression group, negative expression group was earlier (p=0.018,x2=8.016). Joint analysis of the four indicators found it was shorter that the DFS in the more indicator expression groups (p=0.028,x2=10.882).Multivariate analysis found that T stage, lymph node metastasis and Nanog expression were independent risk factor for DFS (p<0.05). Correlation analysis, Nanog was positive correlation with Oct-4and PCNA. PCNA and Ki-67was positive relevant too.(p<0.05).
Conclusion
Nanog, Oct-4, PCNA, Ki-67independent or combined detection may become a judgment postoperative DFS predictor, and the more the expression of indicators may mean that the worse DFS. The combined detection may be more conducive to prognosis. PCNA alone or joint with Ki-67detection may related to the ability of tumor invasion,these markers may be indicators of proliferation and invasion capacity in early gastric cancer. Correlation analysis indicate that there may be a relationship between Nanog and Oct-4; Naong and PCNA; PCNA and Ki-67, and may closely related to the occurrence and development of tumors.
引文
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[1]Garvalov BK, Acker T. Cancer stem cells:a new frame work for the design of tumor therapies [J]. J Mol Med (Berl).2011; 89:95-107.
[2]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acutem yeloid leukaemia after transplantation into SCID mice[J]. Nature.1994;367:645-648.
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[1]Garvalov BK, Acker T. Cancer stem cells:a new frame work for the design of tumor therapies [J]. J Mol Med (Berl).2011; 89:95-107.
[2]Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acutem yeloid leukaemia after transplantation into SCID mice[J]. Nature.1994;367:645-648.
[3]Wright MH, Calcagno AM, Salcido CD, et al. Brcall breast tumors contain distinct CD44+/CD24- and CD133+ cells with cancer stem cell characteristics[J]. Breast Cancer Res.2008;10(1):R10.
[4]Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells[J]. Nature.2007 Jan 4;445(7123):111-5.
[5]Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9[J]. Nature.2006 Aug 17;442(7104):818-22.
[6]Zhang M, Behbod F, Atkinson RL, et al. Identification of tumor-initiating cells in a p53-null mouse model ofbreast cancer[J]. Cancer Res.2008 Jun 15;68(12):4674-82.
[7]Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells[J]. Cancer Res.2007;67:1030-1037.
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[9]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 micro metastases[J].Am J Pathol.1998 Sep;153(3):865-73.
[10]Reachy PA, Karhadkar SS, Berman DM.Tissue repairand steincell renewal in carcinogenesie[J]. Nature.2004;432(7015):324-330.
[11]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 Jan 4;445(7123):106-10.
[12]Enderling H, Hlatky L, Hahnfeldt P. Cancer Stem Cells:A Minor Cancer Subpopulation that Redefines Global Cancer Features. Front Oncol.2013 Apr 15;3:76.
[13]Eyler CE, Rich JN, et al. Survival of the fittest:cancerstem cells in therapeutic resistance and angiogenesis[J]. J Clin Oncol.2008 Jun 10;26(17):2839-45.
[14]Sampieri K, Fodde R, et al. Cancer stem cells and metastasis[J]. Semin Cancer Biol.2012 Jun; 22(3):187-93.
[15]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 Cell.2007 Sep 13;1(3):313-23.
[16]Todaro M, Alea MP, DiStefano AB, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4 [J]. Cell Stem Cell.2007 Oct 11;1(4): 389-402.
[17]Kim J, Chu J, Shen X, et al. An extended transcriptional network for pluripotency of embryonic stem cells[J]. Cell.2008 Mar 21;132(6):1049-61.
[18]Pardo M, Lang B, Yu L, et al. An expanded Oct4 interaction network:implications for stem cell biology, development, and disease[J]. Cell Stem Cell.2010 Apr 2;6(4):382-95.
[19]Yu J, Vodyanik MA, Smuga-Otto K, et al. Induced pluripotent stemcell lines derived from human somatic cells[J]. Science 2007;318:1917-1920.
[20]Chambers I, D Colby, M Robertson, et al. Functional expression cloning of Nanog,a pluripotency sustaining factor in embryonic stem cells[J]. Cell.2003 May 30;113(5): 643-55.
[21]Medvedev SP, Shevchenko Al, Mazurok NA, et al. OCT4 and NANOG are the key genes in the system of pluripotency maintenance in mammalian cells [J]. Genetika.2008 Dec; 44 (12):1589-608.
[22]Mitsui K, Tokuzawa Y, Itoh H, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells[J]. Cell.2003 May 30;113(5):631-42.
[23]Chang DF, Tsai SC, Wang XC, et al. Molcular characterization of the human NANONG protein[J]. Stem Cells.2009,27:812-821.
[24]Wang J, Levasseur DN, Orkin SH. Requirement of Nanog dimerization for stem cell self-renewal and pluripotency[J]. Proc Natl Acad Sci U S A.2008 Apr 29;105(17):6326-31.
[25]Boyer LA, Lee TI, Cole MF, et al. Coretranscriptional regulatory circuitry in human embryonic stem cells[J]. Cell.2005; 122:947-956.
[26]Zbinden M, Duquet A, Lorente-Trigos A, et al. NANOG regulates glioma stem cells and is essential in vivo acting in a cross-functional network with GLIland p53[J]. EMBO J.2010 Aug 4;29(15):2659-74.
[27]Mitsui K, Y Tokuzawa, H Itoh, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells[J]. Cell.2003 May 30;113(5):631-42.
[28]Chambers I, J Silva, D Colby, et al. Nanog safeguards pluripotency and mediates germline development[J]. Nature.2007 Dec 20;450(7173):1230-4.
[29]Hough SR, I Clements, PJ Welch, et al. Differentiation of mouse embryonic stem cells after RNA interference-mediated silencing of OCT4 and Nanog[J]. StemCells.2006 Jun;24(6): 1467-75.
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