基因芯片技术分析前列腺癌发展相关的基因及功能初探
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摘要
人类基因组测序工作的完成使人们可以方便调用任何基因序列,但仅有基因序列并不能解释众多的生物学问题,这要求人们发展一种高通量的技术用于研究基因的生物学功能以及与其他基因相互作用的关系。DNA微阵列技术以其高通量的特点已经在肿瘤生物学的研究中逐渐被采用。由于癌症是源于基因表达谱改变的一种基因疾病,通过DNA微阵列技术研究代表肿瘤发展各阶段细胞之间的基因表达差异将会使人们更好的了解肿瘤的形成和发展过程。
前列腺癌是引起西方男性死亡的主要癌症,而且也是最常见的诊断性癌症。通常,前列腺癌变的速度很慢。如果早期发现并治疗可以得到很好的疗效,然而一旦前列腺癌出现转移就很难进行有效治疗和提高病人的生存率。为了解决上述问题,关键是使用预测性标记物找出哪些前列腺癌病人在其有生之年会进一步发展为转移型前列腺癌。转移型前列腺癌经过了一系列的发展过程其中包括正常前列腺上皮细胞内瘤、局部前列腺癌、侵袭性前列腺癌和转移性前列腺癌。前列腺癌的这些发展阶段包括多个分子的改变,暗示这些发展是通过基因表达差异的改变进行的。
一旦前列腺癌发展为雄激素非依赖性就意味着这些肿瘤细胞的生长不受控制,这个阶段是前列腺癌病人死亡的主要原因。然而几乎所有的转移型前列腺癌病人起初对抗雄激素治疗都有效果,但是在2年内大部分的病人就对抗雄激素治疗失去应答。基因表达的改变和表观遗传的改变被认为是前列腺癌发展为雄激素非依赖性的主要原因[1-4]。为了研究这种发展过程,我们选择使用微阵列技术来研究高恶性、晚期、雄激素非依赖性的前列腺癌细胞系C4-2和低恶性、初期、雄激素依赖性前列腺癌细胞系LNCaP基因表达图谱差异。获得了以下研究结果:
1.选用涵盖18,000多个转录本,代表18,000多个明晰的基因,其中13,000多个为全长基因的美国Affymetrix公司的人类全基因组U133系列芯片,高通量分析了LNCaP/C4-2细胞中基因表达图谱的变化。
2.通过Affymetrix、GenBank,dbEST,and RefSeq等网站对Affymetrix芯片数据进行大量的生物信息学分析和文献调研。其中表达量差异在1倍以上基因658个,表达量差异在2倍以上的基因有260个。175个基因在C4-2细胞中
The vast amount of information available through the human genome project .However, the mere sequence information of the whole genome does not answer all our questions. What is required at this stage is a complete understanding of the function of genes and other parts of the genome so as to uncover how sets of genes and their products work together in normal and diseased conditions. DNA microarrays are some of the most powerful and versatile tools available, and there are several applications of microarray technology in cancer biology. Since cancer is a genetic disease arising from the progressive accumulation of many genetic alternations, identification of differences in the expression profile of tumor cells in comparison to their normal counterpart would provide a better platform for understanding the process of tumor formation and development.
Prostate cancer is a leading cause of cancer-related deaths and the most commonly diagnosed cancer in men in the west. By nature, cancer in the prostate progresses slowly and can be treated effectively when detected early; however, the metastastatic disease presents a major challenge to improve survival rate and treatment efficacy. To overcome this problem, it is critical to identify predictors to distinguish prostate cancers that will progress and metastasize, and to separate them from those that will not progress during the expected lifetime of the patient. Metastatic prostate cancer proceeds through a series of distinct states such as transformation of normal prostatic epithelial cells to preinvasive primary tumor, androgen-dependent invasive cancer, and androgen-independent (AI) metastatic disease. These stages of prostate cancer involve multiple molecular changes some of which can be implicated to alterations in gene expression.
Progression to androgen independence (AI) leading to uncontrolled cell growth is the main cause of death in prostate cancer. While almost all patients with metastatic prostate cancer will initially respond to anti-androgen treatments, the majority will fail hormonal treatments in less than 2 years. Both genetic and epigenetic alterations in
前列腺癌是引起西方男性死亡的主要癌症,而且也是最常见的诊断性癌症。通常,前列腺癌变的速度很慢。如果早期发现并治疗可以得到很好的疗效,然而一旦前列腺癌出现转移就很难进行有效治疗和提高病人的生存率。为了解决上述问题,关键是使用预测性标记物找出哪些前列腺癌病人在其有生之年会进一步发展为转移型前列腺癌。转移型前列腺癌经过了一系列的发展过程其中包括正常前列腺上皮细胞内瘤、局部前列腺癌、侵袭性前列腺癌和转移性前列腺癌。前列腺癌的这些发展阶段包括多个分子的改变,暗示这些发展是通过基因表达差异的改变进行的。
一旦前列腺癌发展为雄激素非依赖性就意味着这些肿瘤细胞的生长不受控制,这个阶段是前列腺癌病人死亡的主要原因。然而几乎所有的转移型前列腺癌病人起初对抗雄激素治疗都有效果,但是在2年内大部分的病人就对抗雄激素治疗失去应答。基因表达的改变和表观遗传的改变被认为是前列腺癌发展为雄激素非依赖性的主要原因[1-4]。为了研究这种发展过程,我们选择使用微阵列技术来研究高恶性、晚期、雄激素非依赖性的前列腺癌细胞系C4-2和低恶性、初期、雄激素依赖性前列腺癌细胞系LNCaP基因表达图谱差异。获得了以下研究结果:
1.选用涵盖18,000多个转录本,代表18,000多个明晰的基因,其中13,000多个为全长基因的美国Affymetrix公司的人类全基因组U133系列芯片,高通量分析了LNCaP/C4-2细胞中基因表达图谱的变化。
2.通过Affymetrix、GenBank,dbEST,and RefSeq等网站对Affymetrix芯片数据进行大量的生物信息学分析和文献调研。其中表达量差异在1倍以上基因658个,表达量差异在2倍以上的基因有260个。175个基因在C4-2细胞中
The vast amount of information available through the human genome project .However, the mere sequence information of the whole genome does not answer all our questions. What is required at this stage is a complete understanding of the function of genes and other parts of the genome so as to uncover how sets of genes and their products work together in normal and diseased conditions. DNA microarrays are some of the most powerful and versatile tools available, and there are several applications of microarray technology in cancer biology. Since cancer is a genetic disease arising from the progressive accumulation of many genetic alternations, identification of differences in the expression profile of tumor cells in comparison to their normal counterpart would provide a better platform for understanding the process of tumor formation and development.
Prostate cancer is a leading cause of cancer-related deaths and the most commonly diagnosed cancer in men in the west. By nature, cancer in the prostate progresses slowly and can be treated effectively when detected early; however, the metastastatic disease presents a major challenge to improve survival rate and treatment efficacy. To overcome this problem, it is critical to identify predictors to distinguish prostate cancers that will progress and metastasize, and to separate them from those that will not progress during the expected lifetime of the patient. Metastatic prostate cancer proceeds through a series of distinct states such as transformation of normal prostatic epithelial cells to preinvasive primary tumor, androgen-dependent invasive cancer, and androgen-independent (AI) metastatic disease. These stages of prostate cancer involve multiple molecular changes some of which can be implicated to alterations in gene expression.
Progression to androgen independence (AI) leading to uncontrolled cell growth is the main cause of death in prostate cancer. While almost all patients with metastatic prostate cancer will initially respond to anti-androgen treatments, the majority will fail hormonal treatments in less than 2 years. Both genetic and epigenetic alterations in
引文
[1] W.A.Schulz1, M.Burchardt , M.V.Cronauer.Molecular biology of prostate cancer [J]. Molecular Human Reproduction 2003 Vol.9, No.8 pp. 437-448
[2] M D Sadar, M Hussain, N Bruchovsky.Prostate cancer: molecular biology of early progression to androgen independence [J]. Endocrine-Related Cancer 1999, 6, 487-502
[3] ROBERT E. REITER, ZHENNEN GU, TETSURO WATABE, et al. Prostate stem cell antigen: A cell surface marker overexpressed in prostate cancer [J]. Proc. Natl. Acad. Sci. USA February 1998, Vol. 95, pp. 1735–1740
[4] S M Powell, V Christiaens1, D Voulgaraki,et al.Mechanisms of androgen receptor signaling via steroid receptor coactivator-1 in prostate [J]. Endocrine-Related Cancer2004, 11, 117–130
[5] Edward P. Gelmann, Searching for the gatekeeper oncogene of prostate cancer [J]. Critical Reviews in Oncology/Hematology 46 ,2003, S11-S20
[6] K.C. Balaji, F.R.C.S, Prema S, et al. Microarray analysis of differential gene expression in androgen independent prostate cancer using a metastatic human prostate cancer cell line model [J]. urologic Oncology: Seminars and Original Investigations 22,2004, 313–320
[7] Alan Mackay , Chris Jones, Tim Dexter, et al. cDNA microarray analysis of genes associated with ERBB2 (HER2/neu) overexpression in human mammary luminal epithelial cells [J]. Oncogene ,2003, 22, 2680–2688
[8] Hai-Tao Wang, Jian-Ping Kong, Fang Ding, et al. Analysis of gene expression profile induced by EMP-1 in esophageal cancer cells using cDNA Microarray [J]. World J Gastroenterol 2003, 9(3):392-398
[9] Chin-Yo Lin, Anders Str?m, Vinsensius Berlian Vega, et al. Discovery of estrogen receptor a target genes and response elements in breast tumor cells [J]. Genome Biology 2004, 5:R66
[10] Norihiko Tsuchiya, Yasushi Kondo,Atsushi Takahashi, et al. Mapping and Gene Expression Profile of the Minimally Overrepresented 8q24 Region in Prostate Cancer [J]. American Journal of Pathology, May 2002, Vol. 160, No. 5
[11] Wang SI, Mukhtar H .Gene expression profile in human prostate LNCaP cancer cells by (-) epigallocatechin-3-gallate [J]. Cancer Letters 182 ,2002, 43–51
[12] David A. C. Simpson, Susan Feeney, Cliona Boyle, et al.Retinal VEGF mRNA measured by SYBR Green I fluorescence: A versatile approach to quantitative PCR [J]. Molecular Vision 2000,6:178-83
[13] Annapaula Giulietti1, Lut Overbergh1, Dirk Valckx, et al.An Overview of Real-Time Quantitative PCR: Applications to Quantify Cytokine Gene Expression [J]. 2001, METHODS 25, 386–401
[14] Thomas D. Schmittgen,Real-Time Quantitative PCR [J]. METHODS 25, 2001, 383–385
[15] Frederique Ponchel, Carmel Toomes, Kieran Bransfield, et al. Real-time PCR based on SYBR-Green I fluorescence: An alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions [J]. BMC Biotechnology ,2003, 3:18
[16] Mangalathu S. Rajeevan, Suzanne D. Vernon,Naovarath Taysavang, et al.Validation of Array-Based Gene Expression Profiles by Real-Time (Kinetic) RT-PCR [J]. Journal of Molecular Diagnostics, February 2001, Vol. 3, No. 1
[17] Ponchel F, Toomes C, Bransfield K , et alReal-time PCR based on SYBR-Green I fluorescence: An alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions [J]. BMC Biotechnology 2003, 3:18
[18] Trudy G. Oliver, Linda L. Grasfeder, Audra L. Carroll, Transcriptional profiling of the Sonic hedgehog response: A critical role for N-myc in proliferation of neuronal precursors [J].Neurosciences, June 10, 2003, vol. 100, no. 12, 7331–7336
[19] Lisa Drew, Robert L.Fine, Anthony J.Raffo, et al.Sustained Activation of Extracellular Signal-Regulated Kinase(ERK)Signaling in Human Prostate Cancer LNCaP Cells Depleted of Androgen [J].The Prostate Journal 2001,Volume3,Number2, 105-107
[20] Farhad Kosari,Yan W. Asmann, John C. Cheville, et al. Cysteine-rich Secretory Protein-3: A Potential Biomarker for Prostate Cancer [J].Cancer Epidemiology, Biomarkers & Prevention, November 2002,Vol. 11,1419–1426
[21] Chun Jing, Carol Beesley, Christopher S. Foster, et al.Identification of the Messenger RNA for Human Cutaneous Fatty Acid-binding Protein as a Metastasis Inducer [J]. CANCER RESEARCH 60, May 1, 2000 2390–2398
[22] Jacqueline Moreno, Aruna V. Krishnan, David Feldman, Molecular mechanisms mediating the anti-proliferative effects of Vitamin D in prostate cancer [J]. Journal of Steroid Biochemistry & Molecular Biology 97, 2005, 31–36
[23] Meena Jaggi, Prema S. Rao, David J. Smith,et al.Protein kinase Cu is down-regulated in androgen-independent prostate cancer [J]. Biochemical and Biophysical Research Communications 307, 2003, 254–260
[24] Rhee SG. REGULATION OF PHOSPHOINOSITIDE-SPECIFIC PHOSPHOLIPASE C[J]. Annu. Rev. Biochem,2001,70:281–312
[25] Liyan Zhuang, Jayoung Kim, Rosalyn M. Adam, et al. Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts [J]. J. Clin. Invest. doi: 10.1172/JCI200519935.
[26] Yun-Fai Chris Lau and Jianqing Zhang. Expression Analysis of Thirty One Y Chromosome Genes in Human Prostate Cancer [J]. MOLECULARCARCINOGENESIS ,2000,27:308-321
[27] Sangeeta K. Cheema, Sandip K. Mishra, Vivek M. Rangnekar, et al. Par-4 Transcriptionally Regulates Bcl-2 through a WT1-binding Site on the bcl-2 Promoter [J]. THE JOuRNAL OF BIOLOGICAL CHEMISTRY, 2003, Vol. 278, No. 22, Issue of May 30, pp. 19995–20005
[28] Haojie Huang, Ofelia L. Zegarra-Moro, Douglas Benson, et al.Androgens repress Bcl-2 expression via activation of the retinoblastoma (RB) protein in prostate cancer cells [J]. Oncogene (2004) 23, 2161–2176
[29] Jin-Tang Dong, Ceshi Chen, Brian G. Stultz, et al. Deletion at 13q21 Is Associated with Aggressive Prostate Cancers [J]. CANCER RESEARCH ,July 15, 2000,60, 3880–3883,
[30] Mark A. Rubin, Sooryanarayana Varambally, Rameen Beroukhim, et al. Overexpression, Amplification, and Androgen Regulation of TPD52 in Prostate Cancer [J]. CANCER RESEARCH 64, June 1, 2004,3814–3822
[31] John DiGiovanni, Kaoru Kiguchi, Anita Frijhoff, et al. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice [J]. PNAS March 28, 2000, vol. 97, no. 7, 3455–3460
[32] Jen-Ming Huang, Tsen-Yin Lin, Donald Chang,et al.Truncated Bcl-2, a potential pre-metastatic marker in prostate cancer [J]. Biochemical and Biophysical Research Communications 306 ,2003, 912–917
[33] Shengjun Qiao and Pentti Tuohimaa .The role of long-chain fatty-acid-CoA ligase 3 in vitamin D3 and androgen control of prostate cancer LNCaP cell growth [J]. Biochemical and Biophysical Research Communications 319 ,2004, 358–368
[34] Asmaa Mamoune, Jareer Kassis, Sourabh Kharait, et al.Du145 human prostate carcinoma invasiveness is modulated by urokinase receptor (uPAR) downstream of epidermal growth factor receptor (EGFR) signaling [J]. Experimental Cell Research 299 ,2004, 91– 100
[35] Steven I. Wang, Hasan Mukhtar.Gene expression profile in human prostate LNCaP cancer cells by (-) epigallocatechin-3-gallate [J]. Cancer Letters 182 ,2002, 43–51
[36] Ratna Chakrabarti, Liza D. Robles, Jane Gibson, et al.Profiling of differential expression of messenger RNA in normal, benign, and metastatic prostate cell lines [J]. Cancer Genetics and Cytogenetics 139,2002, 115–125
[37] Philip A. Cornford,2 Andrew R. Dodson, Keith F. Parsons, et al. Heat Shock Protein Expression Independently Predicts Clinical Outcome in Prostate Cancer [J]. CANCER RESEARCH 60, December 15, 2000,7099–7105
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[2] M D Sadar, M Hussain, N Bruchovsky.Prostate cancer: molecular biology of early progression to androgen independence [J]. Endocrine-Related Cancer 1999, 6, 487-502
[3] ROBERT E. REITER, ZHENNEN GU, TETSURO WATABE, et al. Prostate stem cell antigen: A cell surface marker overexpressed in prostate cancer [J]. Proc. Natl. Acad. Sci. USA February 1998, Vol. 95, pp. 1735–1740
[4] S M Powell, V Christiaens1, D Voulgaraki,et al.Mechanisms of androgen receptor signaling via steroid receptor coactivator-1 in prostate [J]. Endocrine-Related Cancer2004, 11, 117–130
[5] Edward P. Gelmann, Searching for the gatekeeper oncogene of prostate cancer [J]. Critical Reviews in Oncology/Hematology 46 ,2003, S11-S20
[6] K.C. Balaji, F.R.C.S, Prema S, et al. Microarray analysis of differential gene expression in androgen independent prostate cancer using a metastatic human prostate cancer cell line model [J]. urologic Oncology: Seminars and Original Investigations 22,2004, 313–320
[7] Alan Mackay , Chris Jones, Tim Dexter, et al. cDNA microarray analysis of genes associated with ERBB2 (HER2/neu) overexpression in human mammary luminal epithelial cells [J]. Oncogene ,2003, 22, 2680–2688
[8] Hai-Tao Wang, Jian-Ping Kong, Fang Ding, et al. Analysis of gene expression profile induced by EMP-1 in esophageal cancer cells using cDNA Microarray [J]. World J Gastroenterol 2003, 9(3):392-398
[9] Chin-Yo Lin, Anders Str?m, Vinsensius Berlian Vega, et al. Discovery of estrogen receptor a target genes and response elements in breast tumor cells [J]. Genome Biology 2004, 5:R66
[10] Norihiko Tsuchiya, Yasushi Kondo,Atsushi Takahashi, et al. Mapping and Gene Expression Profile of the Minimally Overrepresented 8q24 Region in Prostate Cancer [J]. American Journal of Pathology, May 2002, Vol. 160, No. 5
[11] Wang SI, Mukhtar H .Gene expression profile in human prostate LNCaP cancer cells by (-) epigallocatechin-3-gallate [J]. Cancer Letters 182 ,2002, 43–51
[12] David A. C. Simpson, Susan Feeney, Cliona Boyle, et al.Retinal VEGF mRNA measured by SYBR Green I fluorescence: A versatile approach to quantitative PCR [J]. Molecular Vision 2000,6:178-83
[13] Annapaula Giulietti1, Lut Overbergh1, Dirk Valckx, et al.An Overview of Real-Time Quantitative PCR: Applications to Quantify Cytokine Gene Expression [J]. 2001, METHODS 25, 386–401
[14] Thomas D. Schmittgen,Real-Time Quantitative PCR [J]. METHODS 25, 2001, 383–385
[15] Frederique Ponchel, Carmel Toomes, Kieran Bransfield, et al. Real-time PCR based on SYBR-Green I fluorescence: An alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions [J]. BMC Biotechnology ,2003, 3:18
[16] Mangalathu S. Rajeevan, Suzanne D. Vernon,Naovarath Taysavang, et al.Validation of Array-Based Gene Expression Profiles by Real-Time (Kinetic) RT-PCR [J]. Journal of Molecular Diagnostics, February 2001, Vol. 3, No. 1
[17] Ponchel F, Toomes C, Bransfield K , et alReal-time PCR based on SYBR-Green I fluorescence: An alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions [J]. BMC Biotechnology 2003, 3:18
[18] Trudy G. Oliver, Linda L. Grasfeder, Audra L. Carroll, Transcriptional profiling of the Sonic hedgehog response: A critical role for N-myc in proliferation of neuronal precursors [J].Neurosciences, June 10, 2003, vol. 100, no. 12, 7331–7336
[19] Lisa Drew, Robert L.Fine, Anthony J.Raffo, et al.Sustained Activation of Extracellular Signal-Regulated Kinase(ERK)Signaling in Human Prostate Cancer LNCaP Cells Depleted of Androgen [J].The Prostate Journal 2001,Volume3,Number2, 105-107
[20] Farhad Kosari,Yan W. Asmann, John C. Cheville, et al. Cysteine-rich Secretory Protein-3: A Potential Biomarker for Prostate Cancer [J].Cancer Epidemiology, Biomarkers & Prevention, November 2002,Vol. 11,1419–1426
[21] Chun Jing, Carol Beesley, Christopher S. Foster, et al.Identification of the Messenger RNA for Human Cutaneous Fatty Acid-binding Protein as a Metastasis Inducer [J]. CANCER RESEARCH 60, May 1, 2000 2390–2398
[22] Jacqueline Moreno, Aruna V. Krishnan, David Feldman, Molecular mechanisms mediating the anti-proliferative effects of Vitamin D in prostate cancer [J]. Journal of Steroid Biochemistry & Molecular Biology 97, 2005, 31–36
[23] Meena Jaggi, Prema S. Rao, David J. Smith,et al.Protein kinase Cu is down-regulated in androgen-independent prostate cancer [J]. Biochemical and Biophysical Research Communications 307, 2003, 254–260
[24] Rhee SG. REGULATION OF PHOSPHOINOSITIDE-SPECIFIC PHOSPHOLIPASE C[J]. Annu. Rev. Biochem,2001,70:281–312
[25] Liyan Zhuang, Jayoung Kim, Rosalyn M. Adam, et al. Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts [J]. J. Clin. Invest. doi: 10.1172/JCI200519935.
[26] Yun-Fai Chris Lau and Jianqing Zhang. Expression Analysis of Thirty One Y Chromosome Genes in Human Prostate Cancer [J]. MOLECULARCARCINOGENESIS ,2000,27:308-321
[27] Sangeeta K. Cheema, Sandip K. Mishra, Vivek M. Rangnekar, et al. Par-4 Transcriptionally Regulates Bcl-2 through a WT1-binding Site on the bcl-2 Promoter [J]. THE JOuRNAL OF BIOLOGICAL CHEMISTRY, 2003, Vol. 278, No. 22, Issue of May 30, pp. 19995–20005
[28] Haojie Huang, Ofelia L. Zegarra-Moro, Douglas Benson, et al.Androgens repress Bcl-2 expression via activation of the retinoblastoma (RB) protein in prostate cancer cells [J]. Oncogene (2004) 23, 2161–2176
[29] Jin-Tang Dong, Ceshi Chen, Brian G. Stultz, et al. Deletion at 13q21 Is Associated with Aggressive Prostate Cancers [J]. CANCER RESEARCH ,July 15, 2000,60, 3880–3883,
[30] Mark A. Rubin, Sooryanarayana Varambally, Rameen Beroukhim, et al. Overexpression, Amplification, and Androgen Regulation of TPD52 in Prostate Cancer [J]. CANCER RESEARCH 64, June 1, 2004,3814–3822
[31] John DiGiovanni, Kaoru Kiguchi, Anita Frijhoff, et al. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice [J]. PNAS March 28, 2000, vol. 97, no. 7, 3455–3460
[32] Jen-Ming Huang, Tsen-Yin Lin, Donald Chang,et al.Truncated Bcl-2, a potential pre-metastatic marker in prostate cancer [J]. Biochemical and Biophysical Research Communications 306 ,2003, 912–917
[33] Shengjun Qiao and Pentti Tuohimaa .The role of long-chain fatty-acid-CoA ligase 3 in vitamin D3 and androgen control of prostate cancer LNCaP cell growth [J]. Biochemical and Biophysical Research Communications 319 ,2004, 358–368
[34] Asmaa Mamoune, Jareer Kassis, Sourabh Kharait, et al.Du145 human prostate carcinoma invasiveness is modulated by urokinase receptor (uPAR) downstream of epidermal growth factor receptor (EGFR) signaling [J]. Experimental Cell Research 299 ,2004, 91– 100
[35] Steven I. Wang, Hasan Mukhtar.Gene expression profile in human prostate LNCaP cancer cells by (-) epigallocatechin-3-gallate [J]. Cancer Letters 182 ,2002, 43–51
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