转录因子E2F-1在原发性肺癌中的表达及其临床意义
摘要
目的检测转录因子E2F-1在原发性肺癌组织中的表达水平，并探讨其临床意义。
方法本研究应用免疫组化S-P法，对64例原发性肺癌组织中转录因子E2F-1的表达进行检测，并对临床资料与实验结果之间的关系进行了分析。
结果①64例原发性肺癌中，转录因子E2F-1表达阳性率为76.6％(49／64)，癌旁正常肺组织中转录因子E2F-1表达阳性率为10.9％(7／64)，表达阳性率显著高于癌旁正常肺组织组，统计学分析两组比较有显著性差异(P＜0.01，x~2=53.4)；②Ⅰ期原发性肺癌中，转录因子E2F-1蛋白阳性表达率为75.0％(9／12)，Ⅱ期为73.1％(19／26)，Ⅲ期为78.3％(18／23)，Ⅳ期为100％(3／3)，统计学分析四组间比较无显著性差异(P＞0.05，x~2=1.008)；③鳞状细胞癌中，转录因子E2F-1蛋白阳性表达率为58.3％(14／24)，腺癌为82.6％(19／23)，小细胞肺癌为92.3％(12／13)，大细胞肺癌为100％(4／4)，统计学分析四组间比较有显著性差异(P＜0.05，x~2=7.936)；④高分化型肺癌中，转录因子E2F-1蛋白阳性表达率52.9％(9／17)，中分化型76.0％(19／25)，低分化型95.5％(21／22)，统计学分析，三组间比较有显著性差异(P<0.01，x~2=9.664)；⑤有淋巴结转移组，转录因子E2F-1蛋白阳性表达率为79.5％(31／39)，无淋巴结转移组为72.0％(18／25)，统计学分析两组比较无显著性差异(P>0.05，x~2=0.150)；⑥未侵及脏胸膜组，转录因子E2F-1蛋白阳性表达率为78.6％(22／28)，侵及脏胸膜或周围临近组织组为75.0％(27／36)，统计学分析两组比较无显著性差异(P＞0.05，x~2=0.001)。
结论1．采用免疫组化染色检测原发性肺癌组织中转录因子E2F-1的表达，发现转录因子E2F-1的表达高于正常肺组织。E2F-1蛋白的超表达可能是原发性肺癌发生发展的重要因素之一。
2．免疫组化检测显示，转录因子E2F-1的表达与原发性肺癌的病理类型和分化程度有关：小细胞肺癌和大细胞肺癌中，E2F-1蛋白表达最高，腺癌次之，鳞癌最低；分化程度越低，E2F-1蛋白的表达就越高；但其表达与临床分期、淋巴结转移和肿瘤是否有局部浸润无关。
3．综合分析转录因子E2F-1的表达与临床病理之间的关系，对原发性肺癌的基因诊断、基因治疗、选择合理的治疗方案和判断预后有重要参考价值。
4．总之，原发性肺癌中转录因子E2F-1超表达和反常表达与原发性肺癌的发生发展有关，在肿瘤的发生发展中扮演者重要的角色。
Objective To investigate the expression level and their clinical significance of transcription factor E2F-1 in primary lung carcinoma.
Methods Using S-P immunohistochemistry, the expression of transcription factor E2F-1 was investigated in 64 primary lung carcinoma tissue samples. Statistical analysis was done to analyze the relationship between the clinical data and the experimental results.
Results (1)The positive expression rate of transcription factor E2F-1 in 64 primary lung carcinoma tissues (76.0%) was markedly higher than that in normal lung tissues(10.9%)( P<0.01). ②The positive rate of transcription factor E2F-1 in stage I was 75.0%, that in stage II was 73.1%, in stage III was 78.3%, and in stage IVwas100%, there were no association in the clinical stage. (3)The positive rate of transcription factor E2F-1 in squamous carcinoma was 58.3%, which in adenocarcinoma was 82.6%, in small cell lung carcinoma was 92.3%, and in large cell lung carcinoma was 100%, which were significantly different. ④The positive expression rate of E2F-1 in high, middle and low differentiated lung carcinoma were respectively 52.9%, 76.0%, 95.5%, which were significantly different. (5) But no correlations were found between the positive expression rate of E2F-1 in cases with lymph nodes metastasis(79.5%) and that in those without lymph nodes metastasis(72.0%)( P>0.05). ⑤There was no different between invaded pleura or surrounding tissue group and no invaded visceral pleura group, the positive expression rate of E2F-1 in invaded pleura or surrounding tissue group was 78.6%, in no invaded visceral pleura group was 75.0%. Conclusion The results suggest that transcription factor E2F-1 is excess expression in primary lung carcinoma, the expression of transcription factor E2F-1 was closely associated with clinical pathological types and differentiation degree, but had no relation to clinical stage, whether or not tumor lymph node metastasis and invaded pleura or surrounding tissue. Abnormal expression of transcription factor E2F-1 may be related to the lung tumorigenesis and progression, and may play an important role.
方法本研究应用免疫组化S-P法，对64例原发性肺癌组织中转录因子E2F-1的表达进行检测，并对临床资料与实验结果之间的关系进行了分析。
结果①64例原发性肺癌中，转录因子E2F-1表达阳性率为76.6％(49／64)，癌旁正常肺组织中转录因子E2F-1表达阳性率为10.9％(7／64)，表达阳性率显著高于癌旁正常肺组织组，统计学分析两组比较有显著性差异(P＜0.01，x~2=53.4)；②Ⅰ期原发性肺癌中，转录因子E2F-1蛋白阳性表达率为75.0％(9／12)，Ⅱ期为73.1％(19／26)，Ⅲ期为78.3％(18／23)，Ⅳ期为100％(3／3)，统计学分析四组间比较无显著性差异(P＞0.05，x~2=1.008)；③鳞状细胞癌中，转录因子E2F-1蛋白阳性表达率为58.3％(14／24)，腺癌为82.6％(19／23)，小细胞肺癌为92.3％(12／13)，大细胞肺癌为100％(4／4)，统计学分析四组间比较有显著性差异(P＜0.05，x~2=7.936)；④高分化型肺癌中，转录因子E2F-1蛋白阳性表达率52.9％(9／17)，中分化型76.0％(19／25)，低分化型95.5％(21／22)，统计学分析，三组间比较有显著性差异(P<0.01，x~2=9.664)；⑤有淋巴结转移组，转录因子E2F-1蛋白阳性表达率为79.5％(31／39)，无淋巴结转移组为72.0％(18／25)，统计学分析两组比较无显著性差异(P>0.05，x~2=0.150)；⑥未侵及脏胸膜组，转录因子E2F-1蛋白阳性表达率为78.6％(22／28)，侵及脏胸膜或周围临近组织组为75.0％(27／36)，统计学分析两组比较无显著性差异(P＞0.05，x~2=0.001)。
结论1．采用免疫组化染色检测原发性肺癌组织中转录因子E2F-1的表达，发现转录因子E2F-1的表达高于正常肺组织。E2F-1蛋白的超表达可能是原发性肺癌发生发展的重要因素之一。
2．免疫组化检测显示，转录因子E2F-1的表达与原发性肺癌的病理类型和分化程度有关：小细胞肺癌和大细胞肺癌中，E2F-1蛋白表达最高，腺癌次之，鳞癌最低；分化程度越低，E2F-1蛋白的表达就越高；但其表达与临床分期、淋巴结转移和肿瘤是否有局部浸润无关。
3．综合分析转录因子E2F-1的表达与临床病理之间的关系，对原发性肺癌的基因诊断、基因治疗、选择合理的治疗方案和判断预后有重要参考价值。
4．总之，原发性肺癌中转录因子E2F-1超表达和反常表达与原发性肺癌的发生发展有关，在肿瘤的发生发展中扮演者重要的角色。
Objective To investigate the expression level and their clinical significance of transcription factor E2F-1 in primary lung carcinoma.
Methods Using S-P immunohistochemistry, the expression of transcription factor E2F-1 was investigated in 64 primary lung carcinoma tissue samples. Statistical analysis was done to analyze the relationship between the clinical data and the experimental results.
Results (1)The positive expression rate of transcription factor E2F-1 in 64 primary lung carcinoma tissues (76.0%) was markedly higher than that in normal lung tissues(10.9%)( P<0.01). ②The positive rate of transcription factor E2F-1 in stage I was 75.0%, that in stage II was 73.1%, in stage III was 78.3%, and in stage IVwas100%, there were no association in the clinical stage. (3)The positive rate of transcription factor E2F-1 in squamous carcinoma was 58.3%, which in adenocarcinoma was 82.6%, in small cell lung carcinoma was 92.3%, and in large cell lung carcinoma was 100%, which were significantly different. ④The positive expression rate of E2F-1 in high, middle and low differentiated lung carcinoma were respectively 52.9%, 76.0%, 95.5%, which were significantly different. (5) But no correlations were found between the positive expression rate of E2F-1 in cases with lymph nodes metastasis(79.5%) and that in those without lymph nodes metastasis(72.0%)( P>0.05). ⑤There was no different between invaded pleura or surrounding tissue group and no invaded visceral pleura group, the positive expression rate of E2F-1 in invaded pleura or surrounding tissue group was 78.6%, in no invaded visceral pleura group was 75.0%. Conclusion The results suggest that transcription factor E2F-1 is excess expression in primary lung carcinoma, the expression of transcription factor E2F-1 was closely associated with clinical pathological types and differentiation degree, but had no relation to clinical stage, whether or not tumor lymph node metastasis and invaded pleura or surrounding tissue. Abnormal expression of transcription factor E2F-1 may be related to the lung tumorigenesis and progression, and may play an important role.
引文
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1. Rovesdi I, Rcielel R, Novins JR. Identification of a cellular transcription factor in volved El A trans-activation [J]. Cell, 1986; 45: 219- 228.
2. Helin K, Lees JA, Vidal M, et al. A cDNA encoding a pRb-binding protein with properties of the transcription factor E2F [J]. Cell, 1992; 70: 337- 350.
3. Lees JA, Saito M, Vidal M, et al. The retinoblastoma protein binds to a family of E2F transcription factors [J]. Mol Cell Biol, 1993; 13: 7813- 7825.
4. Ginsberg D, Vairo G, Chittenden T, et al. E2F-4, a new member of the E2F transcription factor family, interacts with pl07 [J]. Genes Dev, 1994; 8: 2665-2679.
5. Hijmans EM, Voorhoeve PM, Beijersbergen RL, et al.E2F-5,a new E2F family member that interacts with p130 in vivo[J]. Mol Cell Biol, 1995; 15: 3082- 3089.
6. Trimarchi JM, Fairchild B, VeronaR, et al.E2F-6, a member of the E2F family that can behave as a transcriptional repressor [J]. Proc Natl Acad Sci USA, 1998;95: 2850- 2855.
7. DeBruin A, Maiti B, Jakoi L, et al. Identification and characterization of E2F-7, a novel mammalian E2F family member capable of blocking cellular proliferation [J]. JBiol Chem, 2003,278(43): 42041- 42049.
8. Yamasaki L, Jacks T, Branson R, et al. Tumor in duction and tissue atrophy in mice lacking E2F-1 [J]. Cell, 1996, 85: 537- 548.
9. Huber HE, Edwards G, Goodhard PT, et al. Transcription factor E2F binds DNA as a heterodimer [J]. Proc Natl Acad Sci USA, 1993; 90: 3525- 3529.
10. Hiebert SW, Bker M, Azizkham J, et al. Roleof E2F transcription factor in EIA-mediated transactivation of cellular genes [J]. J Virol, 1991; 65: 3547- 3552.
11. Krek W, Xu G, Livingston DM. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of a S phase checkpoint [J]. Cell, 1995; 83(7): 1149-1158.
12. Field SJ, Tsai FY, Kuo F, et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation [J]. Cell, 1996; 85: 549- 561.
13. Humbert PO, Verona R, Trimarchi JM, et al. E2F-3 is critical for normal cellular proliferation [J]. Genes Dev, 2000; 14: 690- 703.
14. Nevins JR. Toward an understanding of the functional complexity of the E2F and retinoblastoma families [J]. Cell Growth Differ, 1998; 9: 585- 593.
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16. Muller H, Helin K. The E2F transcription factors: key regulators of cell proliferation [J]. Biochim Biophys Acta, 2000, 1470(1): Ml- 12. Review.
17. Krek W, Xu G, Livingston D. CyclinA-kinase regulation of E2F-1 DNA binding fuction underlies suppression of a Sphase checkpoint [J]. Cell, 1995, 83: 1149-1158.
18. Beijersbergen RL, Bemards R. Cell cycle regulation by the retinoblastoma family of growth inhibitory proteins [J]. Biochem Biophys Acta, 1996, 1287: 103-120.
19. Hou ST, Cowan E, Dostanic S, et al. increased expression of the transcription factor E2F-1 during dopamine-evoked, caspase-3-mediated apoptosis in rat cortical neurons [J]. Neurosci Lett, 2001; 306(3): 153-156
20. Shu HK, Julin CM, Furman F, et al. Overexpression of E2F-1 in glioma-derived cell lines induces a p53-independent apoptosis that is further enhanced by ionizing radiation [J]. Neuro-Oncol, 2000; 2(1): 16- 21.
21. Seth JF, Fong-YT, Frank Kuo, et al. E2F-1 function in mice to promote apoptosis and suppress proliferation [J]. Cell, 1996, 85: 549- 561.
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25. Pierce AM, Schneider-Broussard R, Gimenez-Conti IB, et al. E2F-1 has both oncogenic and tumor-suppressive properties in a transgenic model [J]. Mol Cell Biol, 1999; 19(9): 6408-6414.
26. Rotmbehler RJ, Rogers PM, Conti CJ, et al. Inactivation of E2F-1 enhances tumorigenesis in a Myc transgenic model [J]. Cancer Res, 2002; 62(11): 3276-3281.
27. Rodicker F, Stiewe T, Zimmermarm S, et al. Therapeutic efficacy of E2F-1 in pancreatic cancer correlates with TP73 induction [J]. Cancer Res, 2001; 61(19): 7052-7055.
28. Elliott MJ, Baker JD, Dong YB, et al. Inhibition of cyelin A kinase activity in E2F-1 ehemogene therapy of colon cancer [J]. Tumor Biol, 2002; 23(6): 324-326.
29. Yang XH, Siadek TL. Over expression of the E2F-1 transcription factor gene mediates cell transformation [J]. Gene Expr, 1995, 4: 195-204.
30. DeMuth JP, Jackson CM, waever DA, et al. The gene Expression index c-niyc x E2F-1/p21 is lighly predictiue of malignant phenofgpe in human bronchial epithelial cells [J]. Am J Respir cell mol Biel, 1998, 19(1): 18-24.
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32．刘小琦，宾晓农，曾波航，等．E2F-1基因和RB基因在人肺组织中的表达及临床意义[J]．广州医学院报，2005，33(6)：53-55．
33．田燕雏，葛炳生，张波，等．pRb，E2F-1在肺神经内分泌肿瘤中的表达及其临床意义[J]．中华医学杂志，2001，81(4)：219-221．
34．林福地，谢庆祥，张闽峰，等．转录因子E2F-1在肺癌组织中表达的意义[J]．肿瘤防治杂志，2003，10(12)：1263-1264．
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21. Hou ST, Cowan E, Dostanic S, et al. Increased expression of the transcription factor E2F-1 during dopamine-evoked, caspase-3-mediated apoptosis in rat cortical neurons [J]. Neurosci Lett, 2001; 306(3): 153-156
22. Shu HK, Julin CM, Furman F, et al. Overexpression of E2F-1 in glioma-derived cell lines induces a p53-independent apoptosis that is further enhanced by ionizing radiation [J]. Neuro-Oncol, 2000; 2(1): 16- 21.
23. Seth JF, Fong-YT, Frank Kuo, et al. E2F-1 function in mice to promote apoptosis and suppress proliferation [J]. Cell, 1996, 85: 549- 561.
24. Vorburger SA, Pataer A, Yoshida K, et al. The mitochondrial apoptosis-inducing factor plays a role in E2F-1-induced apoptosis in human colon cancer cells [J]. Ann Surg Oncol, 2003; 10(3): 314- 322.
25. Chen Q, Hung FC, Fromm L, et al. Induction of cell cycle entry and cell death in postmitotic lens fiber cells by overexpression of E2F-1 or E2F-2 [J]. Invest Ophthalmol Vis Sci, 2000; 41(13): 4223- 4231.
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27. Pierce AM, Schneider-Broussard R, Gimenez-Conti IB, et al. E2F-1 has both oncogenic and tumor-suppressive properties in a transgenic model [J]. Mol Cell Biol, 1999; 19(9): 6408- 6414.
28. Rounbehler RJ, Rogers PM, Conti CJ, et al. Inactivation of E2F-1 enhances tumorigenesis in a Myc transgenic model [J]. Cancer Res, 2002; 62(11): 3276-3281.
29. Rodicker F, Stiewe T, Zimmermann S, et al. Therapeutic efficacy of E2F-1 in pancreatic cancer correlates with TP73 induction [J]. Cancer Res, 2001; 61(19):7052-7055.
30. Elliott MJ, Baker JD, Dong YB, et al. Inhibition of cyclin A kinase activity in E2F-1 chemogene therapy of colon cancer [J]. Tumor Biol, 2002; 23(6): 324-326.
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41．钟鸣，王洁，张波，等．人成釉细胞瘤中pRb和E2F-1表达与端粒酶活性的关系[J]．中华口腔医学杂志，2004，39(5)：406-409．
42．牛昀，刘铁菊，李好，等．乳腺乳头状瘤病中4种细胞周期调控因子的检测及临床意义[J]．中华医学杂志，2003，83(20)：1769-1773．
43．夏可义，肖强，陆云飞，等．胃癌中E2F-1的表达及其临床意义[J]．中国肿瘤临床与康复，2005，12(2)：124-126．
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45．马俊红，白莉，陈丽瑛．细胞周期素Ep21，转录因子E2F-1在尖锐湿疣中的表达[J]．中国皮肤性病学杂志，2003，5(17)：304-306．
46．姚玉霞，姜慧卿，任锡玲，等．幽门螺杆菌感染患者胃黏膜上皮细胞E2F-1表达与其增殖凋亡的相关性研究[J]．中华消化内镜杂志，2004，21(6)：390-392．
47．岳丽玲，吴国新，于海涛，等．结直肠癌组织中E2F-1!Bcl-2蛋白的表达及其临床意义[J]．医学研究杂志，2006，35(3)：40-42．
48. DeMuth JP, Jackson CM, waever DA, et al. The gene Expression index c-niyc x E2F-1/p21 is lighly predictiue of malignant phenofgpe in human bronchial epithelial cells [J]. Am J Respir cell mol Biel, 1998, 19(1): 18-24.
49．刘小琦，宾晓农，曾波航，等．E2F-1基因和RB基因在人肺组织中的表达及临床意义[J]．广州医学院报，2005，33(6)：53-55．
50．田燕雏，葛炳生，张波，等．pRb，E2F-1在肺神经内分泌肿瘤中的表达及其临床意义[J]．中华医学杂志，2001，81(4)：219-221．
51．林福地，谢庆祥，张闽峰，等．转录因子E2F-1在肺癌组织中表达的意义[J]．肿瘤防治杂志，2003，10(12)：1263-1264．
1. Rovesdi I, Rcielel R, Novins JR. Identification of a cellular transcription factor in volved El A trans-activation [J]. Cell, 1986; 45: 219- 228.
2. Helin K, Lees JA, Vidal M, et al. A cDNA encoding a pRb-binding protein with properties of the transcription factor E2F [J]. Cell, 1992; 70: 337- 350.
3. Lees JA, Saito M, Vidal M, et al. The retinoblastoma protein binds to a family of E2F transcription factors [J]. Mol Cell Biol, 1993; 13: 7813- 7825.
4. Ginsberg D, Vairo G, Chittenden T, et al. E2F-4, a new member of the E2F transcription factor family, interacts with pl07 [J]. Genes Dev, 1994; 8: 2665-2679.
5. Hijmans EM, Voorhoeve PM, Beijersbergen RL, et al.E2F-5,a new E2F family member that interacts with p130 in vivo[J]. Mol Cell Biol, 1995; 15: 3082- 3089.
6. Trimarchi JM, Fairchild B, VeronaR, et al.E2F-6, a member of the E2F family that can behave as a transcriptional repressor [J]. Proc Natl Acad Sci USA, 1998;95: 2850- 2855.
7. DeBruin A, Maiti B, Jakoi L, et al. Identification and characterization of E2F-7, a novel mammalian E2F family member capable of blocking cellular proliferation [J]. JBiol Chem, 2003,278(43): 42041- 42049.
8. Yamasaki L, Jacks T, Branson R, et al. Tumor in duction and tissue atrophy in mice lacking E2F-1 [J]. Cell, 1996, 85: 537- 548.
9. Huber HE, Edwards G, Goodhard PT, et al. Transcription factor E2F binds DNA as a heterodimer [J]. Proc Natl Acad Sci USA, 1993; 90: 3525- 3529.
10. Hiebert SW, Bker M, Azizkham J, et al. Roleof E2F transcription factor in EIA-mediated transactivation of cellular genes [J]. J Virol, 1991; 65: 3547- 3552.
11. Krek W, Xu G, Livingston DM. Cyclin A-kinase regulation of E2F-1 DNA binding function underlies suppression of a S phase checkpoint [J]. Cell, 1995; 83(7): 1149-1158.
12. Field SJ, Tsai FY, Kuo F, et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation [J]. Cell, 1996; 85: 549- 561.
13. Humbert PO, Verona R, Trimarchi JM, et al. E2F-3 is critical for normal cellular proliferation [J]. Genes Dev, 2000; 14: 690- 703.
14. Nevins JR. Toward an understanding of the functional complexity of the E2F and retinoblastoma families [J]. Cell Growth Differ, 1998; 9: 585- 593.
15. Harper JW, Elledge SL, Keyomarsi K, et al. Inhibition of cyclin-dependent kinases by P21 [J]. Mol Biol Cell, 1995; 6: 387- 400.
16. Muller H, Helin K. The E2F transcription factors: key regulators of cell proliferation [J]. Biochim Biophys Acta, 2000, 1470(1): Ml- 12. Review.
17. Krek W, Xu G, Livingston D. CyclinA-kinase regulation of E2F-1 DNA binding fuction underlies suppression of a Sphase checkpoint [J]. Cell, 1995, 83: 1149-1158.
18. Beijersbergen RL, Bemards R. Cell cycle regulation by the retinoblastoma family of growth inhibitory proteins [J]. Biochem Biophys Acta, 1996, 1287: 103-120.
19. Hou ST, Cowan E, Dostanic S, et al. increased expression of the transcription factor E2F-1 during dopamine-evoked, caspase-3-mediated apoptosis in rat cortical neurons [J]. Neurosci Lett, 2001; 306(3): 153-156
20. Shu HK, Julin CM, Furman F, et al. Overexpression of E2F-1 in glioma-derived cell lines induces a p53-independent apoptosis that is further enhanced by ionizing radiation [J]. Neuro-Oncol, 2000; 2(1): 16- 21.
21. Seth JF, Fong-YT, Frank Kuo, et al. E2F-1 function in mice to promote apoptosis and suppress proliferation [J]. Cell, 1996, 85: 549- 561.
22. Vorburger SA, Pataer A, Yoshida K, et al. The mitochondrial apoptosis-inducing factor plays a role in E2F-1-induced apoptosis in human colon cancer cells [J].Ann Surg Oncol, 2003; 10(3): 314- 322
23. Chen Q, Hung FC, Fromm L, et al. Induction of cell cycle entry and cell death in postmitotic lens fiber cells by overexpression of E2F-1 or E2F-2[J]. Invest Ophthalmol Vis Sci, 2000; 41(13): 4223- 4231.
24. Pierce AM, Gimenez-Conti IB, Schneider-Broussard R, et al. Proc Natl Acad Sci USA, 1998; 95: 8858-8863.
25. Pierce AM, Schneider-Broussard R, Gimenez-Conti IB, et al. E2F-1 has both oncogenic and tumor-suppressive properties in a transgenic model [J]. Mol Cell Biol, 1999; 19(9): 6408-6414.
26. Rotmbehler RJ, Rogers PM, Conti CJ, et al. Inactivation of E2F-1 enhances tumorigenesis in a Myc transgenic model [J]. Cancer Res, 2002; 62(11): 3276-3281.
27. Rodicker F, Stiewe T, Zimmermarm S, et al. Therapeutic efficacy of E2F-1 in pancreatic cancer correlates with TP73 induction [J]. Cancer Res, 2001; 61(19): 7052-7055.
28. Elliott MJ, Baker JD, Dong YB, et al. Inhibition of cyelin A kinase activity in E2F-1 ehemogene therapy of colon cancer [J]. Tumor Biol, 2002; 23(6): 324-326.
29. Yang XH, Siadek TL. Over expression of the E2F-1 transcription factor gene mediates cell transformation [J]. Gene Expr, 1995, 4: 195-204.
30. DeMuth JP, Jackson CM, waever DA, et al. The gene Expression index c-niyc x E2F-1/p21 is lighly predictiue of malignant phenofgpe in human bronchial epithelial cells [J]. Am J Respir cell mol Biel, 1998, 19(1): 18-24.
31. ]Nicholson SA, Okby NT, Khan MA, et al. Alterations of p14AFR, p53, and p73 genes involved in the E2F-1-mediated apoptotic pathways in non-small cell lung carcinoma [J]. Cancer Res, 2001, 61 (14): 5636-5643.
32．刘小琦，宾晓农，曾波航，等．E2F-1基因和RB基因在人肺组织中的表达及临床意义[J]．广州医学院报，2005，33(6)：53-55．
33．田燕雏，葛炳生，张波，等．pRb，E2F-1在肺神经内分泌肿瘤中的表达及其临床意义[J]．中华医学杂志，2001，81(4)：219-221．
34．林福地，谢庆祥，张闽峰，等．转录因子E2F-1在肺癌组织中表达的意义[J]．肿瘤防治杂志，2003，10(12)：1263-1264．