REST在乳腺癌中的功能研究
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摘要
研究背景及目的：乳腺癌是世界范围内妇女最常见的恶性肿瘤之一,严重威胁着女性的身心健康和生命。乳腺癌的发生为多基因参与和多阶段协同作用的结果,其中细胞内癌基因的活化和/或抑癌基因的失活是导致乳腺癌发生的重要原因。研究新的抑癌基因对乳腺癌产生的作用及引起的生物学特性的改变,对于阐明乳腺癌的发病机制、指导临床治疗具有重要意义。研究发现,在10-30%的乳腺癌中检测到肿瘤细胞出现神经内分泌分化现象,而这一现象出现的原因及意义仍不十分明确。
抑制元件-1沉默转录因子REST在正常上皮组织中广泛表达,具有抑制细胞中神经内分泌相关基因表达的作用,其功能缺失与前列腺癌细胞出现神经内分泌分化有关；最近有研究报道REST具有抑制肿瘤发生的作用,REST基因缺失或突变与小细胞肺癌、前列腺癌、肠癌等许多肿瘤的发生密切相关,将正常乳腺上皮细胞中REST功能抑制后可引起细胞出现锚定非依赖性生长的恶性转变。那么,REST功能异常是否与乳腺癌的发生有关,是否参与了乳腺癌细胞神经内分泌分化的过程,目前国内外未见相关报道。
本研究通过分析REST在乳腺癌标本中的表达及意义、揭示REST在乳腺癌细胞中的作用,以期进一步完善乳腺癌的发病机制,为乳腺癌的治疗提供新的靶标及为乳腺癌的预后判断提供新的科学依据。
方法：收集乳腺正常组织、良性病变及乳腺癌标本,通过免疫组织化学的方法检测各组织中REST、Syn、ER、PR、Her-2蛋白的表达情况。采用χ2检验,Spearman's等级相关分析等统计方法,分析REST在乳腺癌的发生、神经内分泌分化及转移中的可能作用。
进一步研究REST在乳腺癌细胞系中的作用,首先,采用RNA干扰技术稳定干扰内源性高表达REST细胞中REST的表达,通过RT-PCR、Western Blot等方法鉴定稳定干扰REST的细胞系；生长曲线、平板克隆及软琼脂集落克隆形成率检测细胞的增殖；Hochest凋亡染色、流式细胞术检测细胞凋亡；单细胞凝胶电泳、MTT药敏试验检测细胞对化疗药物的敏感性。其次,通过外源性REST转染重建REST低表达细胞中REST的表达,流式细胞术检测细胞凋亡改变；透射电子显微镜技术检测细胞损伤情况；侵袭小室检测细胞的迁移与侵袭能力改变。Western Blot检测与增殖、凋亡及侵袭相关基因的表达情况。
结果：免疫组织化学结果显示,乳腺癌组织中REST的阳性表达率为69.1%,较非癌性病变的乳腺组织明显下降,差异具有统计学意义(p<0.05)。同时,在乳腺癌标本中比较分析腋窝淋巴结转移组与未转移组,发现前者REST的表达阳性率也显著低于后者；本研究检测的68例乳腺癌组织中有22.1%的乳腺癌组织出现神经内分泌分化现象,而且乳腺癌组织神经内分泌分化现象的出现与REST蛋白的表达呈负相关(p<0.01,R=-0.412)；REST蛋白的表达与ER、PR及Her-2的表达无明显关联(p>0.05)；
稳定沉默内源性高表达REST的乳腺癌细胞MCF-7中REST基因表达后,细胞生长加快,细胞周期G1/S期进程加速,细胞克隆形成能力及停泊非依赖性生长能力增强,与增殖有关的蛋白PI3K表达上调,Akt蛋白磷酸化水平升高；稳定沉默MCF-7细胞中REST的表达后,细胞的凋亡抗性增加,细胞内与凋亡相关的蛋白Caspase-7活性降低、c-Jun蛋白的磷酸化水平下降；肿瘤细胞对化疗药物敏感性下降,抗凋亡基因Bcl-2表达上调；重建REST低表达细胞MDA-MB-231细胞中REST的表达后,乳腺癌细胞的凋亡率上升；化疗药物作用后,细胞的损伤程度加重；增强MDA-MB-231细胞内REST的表达后,乳腺癌细胞的迁移、侵袭能力受到抑制,而且细胞内金属基质蛋白酶MMP-9的表达下调。
1、首次揭示REST:在乳腺癌中的表达下降,证明REST表达下降与乳腺癌的转移及乳腺癌细胞神经内分泌分化的发生有关；且NED可能促进肿瘤的转移；
2、REST功能缺失后通过活化PI3K/Akt信号通路,促进细胞生长增殖；通过抑制Caspase-7和c-Jun的活化增加细胞的凋亡抗性；说明在乳腺癌细胞中REST蛋白具有抑制细胞增殖和启动细胞凋亡等抑瘤功能,
3、REST沉默后可上调抗凋亡基因Bcl-2的表达介导乳腺癌细胞耐药,提示REST可能与肿瘤耐药有关。
4、首次证实REST蛋白通过下调金属基质蛋白酶MMP-9的表达进而抑制乳腺癌细胞侵袭转移。
Background and Objective:Breast cancer is the most common cancer of women and the second leading cause of female cancer mortality in the world. The mortality rate of breast cancer could be lowered by identification of novel molecular markers of early breast cancer and understanding the molecular mechanisms of the early events of breast cancer. It has been reported that there are 10-30% breast cancer show the character of neuroendocrine differentiation(NED). But the mechanism is still unclear. RE1 silencing transcription factor (REST) is generally expressed in all of epithelial cell, who in charge of the expression of neuronal gene. Dysfunction of REST took part in the NED of prostate cancer. And recently, the tumor suppression role of REST is identified. REST expression was recently shown to be absent in many other cancers, such as small cell lung cancer (SCLC), colorectal cancer and prostate cancer. Blockade of REST function in the epithelial cells is found to cause a transformation phenotype, such as anchorage-independent growth. Neither REST take part in the development of breast cancer nor REST may have relationship with the NED of breast cancer has been reported.
The aim of this study is to investigate the expression of REST in breast cancer and analysis the possible role of REST in breast cancer. The results could contribute to elucidate the mechanism of tumorigenesis. It could provide a new target for the treatment of breast cancer. And also provide a new prognosis factor for breast cancer.
Methods:The samples were collected. And the expression of REST, Syn, ER, PR and Her-2 were detected by Immunohistochemistry. The expression of REST and the relationship of them in the breast cancer were analyzed byχ2 test and Spearman's rank correlation analysis. To further investigate the possible role of REST in breast cancer cell, the endogenous expression of REST was shut-down by RNAi. The cell line in which REST expression was stable silenced was identified by RT-PCR and Western Blot. Growth curve and colony formation were used to detect the cell proliferation. The apoptosis of cell was detected by Hochest 33258 stain and Flow Cytometry. Single cell gel electrophoresis and MTT chemotherapy sensitivity were used to analysis the sensitivity of cell to anticancer drug. Moreover, reconstitution of REST in breast cancer cells by transgene. Flow Cytometry and Transmission electron microscope were used to analysis the apoptosis and damage of cells. The capability of migration and metastasis were detected by Transwell analysis. Western Blot was used to detect the expression of genes that associated with proliferation, apoptosis and metastasis.
Results:The positive expression of REST was only 69.1% in breast cancer. The difference was significant between the breast cancer and benign breast samples (p<0.05). Also the positive percent was also declined in breast cancer in which the metastasis was happened. There was 22.1% of breast cancer showed the character of neuroendocrine differentiation(NED). Furthermore, there was negative relationship between the expression of REST and NED (p<0.01, R=-0.412). There was no significant relation among the expression of REST and ER, PR, Her-2(p>0.05).
The proliferation of MCF-7 cell, in which the endogenous expression of REST was relatively high, was enhanced when REST was shut down. The expression of PI3K and p-Akt were enhanced. Also the apoptosis of MCF-7cell was reduced when REST was shut down. And concomitance with activity of Caspase-7 and c-Jun were reduced. Loss of REST expression resulted in a reduction chemosensitivity to anticancer drug. And the increasing in Bcl-2 expression was detected.The apoptosis was increased when reconstitution of REST in breast cancer cell MDA-MB-231, in which the expression of REST was relatively low. The metastasis ability of MDA-MB-231 cell was restrained when the expression of REST was up-regulated, in concomitant with the suppression of MMP-9 expression.
1. The expression of REST was down-regulated in breast cancer. There was some relationship between the reduced expression of REST and the metastasis of breast cancer. The reduced expressions of REST maybe take part in the development of NED in the breast cancer. And the NED of breast cancer may promote the metastasis of breast cancer.
2. The PI3K/Akt pathway was activated when the expression of RSET was shut down. This maybe results in proliferation of cells. And the apoptosis was reduced concomitance with the activation of Caspase-7 and c-Jun was decreased. All of these indicated that the role of REST was suppression of proliferation and induction of apoptosis.
3. REST mediated the drug resistance in the breast cancer through increasing the expression of Bcl-2. REST maybe take part in chemotherapy resistance of breast cancer.
4. REST attenuated the capability of metastasis of breast cancer cell by suppressing the expression of MMP-9.
抑制元件-1沉默转录因子REST在正常上皮组织中广泛表达,具有抑制细胞中神经内分泌相关基因表达的作用,其功能缺失与前列腺癌细胞出现神经内分泌分化有关；最近有研究报道REST具有抑制肿瘤发生的作用,REST基因缺失或突变与小细胞肺癌、前列腺癌、肠癌等许多肿瘤的发生密切相关,将正常乳腺上皮细胞中REST功能抑制后可引起细胞出现锚定非依赖性生长的恶性转变。那么,REST功能异常是否与乳腺癌的发生有关,是否参与了乳腺癌细胞神经内分泌分化的过程,目前国内外未见相关报道。
本研究通过分析REST在乳腺癌标本中的表达及意义、揭示REST在乳腺癌细胞中的作用,以期进一步完善乳腺癌的发病机制,为乳腺癌的治疗提供新的靶标及为乳腺癌的预后判断提供新的科学依据。
方法：收集乳腺正常组织、良性病变及乳腺癌标本,通过免疫组织化学的方法检测各组织中REST、Syn、ER、PR、Her-2蛋白的表达情况。采用χ2检验,Spearman's等级相关分析等统计方法,分析REST在乳腺癌的发生、神经内分泌分化及转移中的可能作用。
进一步研究REST在乳腺癌细胞系中的作用,首先,采用RNA干扰技术稳定干扰内源性高表达REST细胞中REST的表达,通过RT-PCR、Western Blot等方法鉴定稳定干扰REST的细胞系；生长曲线、平板克隆及软琼脂集落克隆形成率检测细胞的增殖；Hochest凋亡染色、流式细胞术检测细胞凋亡；单细胞凝胶电泳、MTT药敏试验检测细胞对化疗药物的敏感性。其次,通过外源性REST转染重建REST低表达细胞中REST的表达,流式细胞术检测细胞凋亡改变；透射电子显微镜技术检测细胞损伤情况；侵袭小室检测细胞的迁移与侵袭能力改变。Western Blot检测与增殖、凋亡及侵袭相关基因的表达情况。
结果：免疫组织化学结果显示,乳腺癌组织中REST的阳性表达率为69.1%,较非癌性病变的乳腺组织明显下降,差异具有统计学意义(p<0.05)。同时,在乳腺癌标本中比较分析腋窝淋巴结转移组与未转移组,发现前者REST的表达阳性率也显著低于后者；本研究检测的68例乳腺癌组织中有22.1%的乳腺癌组织出现神经内分泌分化现象,而且乳腺癌组织神经内分泌分化现象的出现与REST蛋白的表达呈负相关(p<0.01,R=-0.412)；REST蛋白的表达与ER、PR及Her-2的表达无明显关联(p>0.05)；
稳定沉默内源性高表达REST的乳腺癌细胞MCF-7中REST基因表达后,细胞生长加快,细胞周期G1/S期进程加速,细胞克隆形成能力及停泊非依赖性生长能力增强,与增殖有关的蛋白PI3K表达上调,Akt蛋白磷酸化水平升高；稳定沉默MCF-7细胞中REST的表达后,细胞的凋亡抗性增加,细胞内与凋亡相关的蛋白Caspase-7活性降低、c-Jun蛋白的磷酸化水平下降；肿瘤细胞对化疗药物敏感性下降,抗凋亡基因Bcl-2表达上调；重建REST低表达细胞MDA-MB-231细胞中REST的表达后,乳腺癌细胞的凋亡率上升；化疗药物作用后,细胞的损伤程度加重；增强MDA-MB-231细胞内REST的表达后,乳腺癌细胞的迁移、侵袭能力受到抑制,而且细胞内金属基质蛋白酶MMP-9的表达下调。
1、首次揭示REST:在乳腺癌中的表达下降,证明REST表达下降与乳腺癌的转移及乳腺癌细胞神经内分泌分化的发生有关；且NED可能促进肿瘤的转移；
2、REST功能缺失后通过活化PI3K/Akt信号通路,促进细胞生长增殖；通过抑制Caspase-7和c-Jun的活化增加细胞的凋亡抗性；说明在乳腺癌细胞中REST蛋白具有抑制细胞增殖和启动细胞凋亡等抑瘤功能,
3、REST沉默后可上调抗凋亡基因Bcl-2的表达介导乳腺癌细胞耐药,提示REST可能与肿瘤耐药有关。
4、首次证实REST蛋白通过下调金属基质蛋白酶MMP-9的表达进而抑制乳腺癌细胞侵袭转移。
Background and Objective:Breast cancer is the most common cancer of women and the second leading cause of female cancer mortality in the world. The mortality rate of breast cancer could be lowered by identification of novel molecular markers of early breast cancer and understanding the molecular mechanisms of the early events of breast cancer. It has been reported that there are 10-30% breast cancer show the character of neuroendocrine differentiation(NED). But the mechanism is still unclear. RE1 silencing transcription factor (REST) is generally expressed in all of epithelial cell, who in charge of the expression of neuronal gene. Dysfunction of REST took part in the NED of prostate cancer. And recently, the tumor suppression role of REST is identified. REST expression was recently shown to be absent in many other cancers, such as small cell lung cancer (SCLC), colorectal cancer and prostate cancer. Blockade of REST function in the epithelial cells is found to cause a transformation phenotype, such as anchorage-independent growth. Neither REST take part in the development of breast cancer nor REST may have relationship with the NED of breast cancer has been reported.
The aim of this study is to investigate the expression of REST in breast cancer and analysis the possible role of REST in breast cancer. The results could contribute to elucidate the mechanism of tumorigenesis. It could provide a new target for the treatment of breast cancer. And also provide a new prognosis factor for breast cancer.
Methods:The samples were collected. And the expression of REST, Syn, ER, PR and Her-2 were detected by Immunohistochemistry. The expression of REST and the relationship of them in the breast cancer were analyzed byχ2 test and Spearman's rank correlation analysis. To further investigate the possible role of REST in breast cancer cell, the endogenous expression of REST was shut-down by RNAi. The cell line in which REST expression was stable silenced was identified by RT-PCR and Western Blot. Growth curve and colony formation were used to detect the cell proliferation. The apoptosis of cell was detected by Hochest 33258 stain and Flow Cytometry. Single cell gel electrophoresis and MTT chemotherapy sensitivity were used to analysis the sensitivity of cell to anticancer drug. Moreover, reconstitution of REST in breast cancer cells by transgene. Flow Cytometry and Transmission electron microscope were used to analysis the apoptosis and damage of cells. The capability of migration and metastasis were detected by Transwell analysis. Western Blot was used to detect the expression of genes that associated with proliferation, apoptosis and metastasis.
Results:The positive expression of REST was only 69.1% in breast cancer. The difference was significant between the breast cancer and benign breast samples (p<0.05). Also the positive percent was also declined in breast cancer in which the metastasis was happened. There was 22.1% of breast cancer showed the character of neuroendocrine differentiation(NED). Furthermore, there was negative relationship between the expression of REST and NED (p<0.01, R=-0.412). There was no significant relation among the expression of REST and ER, PR, Her-2(p>0.05).
The proliferation of MCF-7 cell, in which the endogenous expression of REST was relatively high, was enhanced when REST was shut down. The expression of PI3K and p-Akt were enhanced. Also the apoptosis of MCF-7cell was reduced when REST was shut down. And concomitance with activity of Caspase-7 and c-Jun were reduced. Loss of REST expression resulted in a reduction chemosensitivity to anticancer drug. And the increasing in Bcl-2 expression was detected.The apoptosis was increased when reconstitution of REST in breast cancer cell MDA-MB-231, in which the expression of REST was relatively low. The metastasis ability of MDA-MB-231 cell was restrained when the expression of REST was up-regulated, in concomitant with the suppression of MMP-9 expression.
1. The expression of REST was down-regulated in breast cancer. There was some relationship between the reduced expression of REST and the metastasis of breast cancer. The reduced expressions of REST maybe take part in the development of NED in the breast cancer. And the NED of breast cancer may promote the metastasis of breast cancer.
2. The PI3K/Akt pathway was activated when the expression of RSET was shut down. This maybe results in proliferation of cells. And the apoptosis was reduced concomitance with the activation of Caspase-7 and c-Jun was decreased. All of these indicated that the role of REST was suppression of proliferation and induction of apoptosis.
3. REST mediated the drug resistance in the breast cancer through increasing the expression of Bcl-2. REST maybe take part in chemotherapy resistance of breast cancer.
4. REST attenuated the capability of metastasis of breast cancer cell by suppressing the expression of MMP-9.
引文
[1]Coughlin SS, Ekwueme DU. Breast cancer as a global health concern. Cancer Epidemiol 2009,33(5):315-318
[2]Knaul F, Bustreo F, Ha E, et al. Breast cancer:why link early detection to reproductive health interventions in developing countries? Salud Publica Mex 2009, 51 Suppl2:s220-227
[3]Micheli A, Sanz N, Mwangi-Powell F, et al. International collaborations in cancer control and the Third International Cancer Control Congress. Tumori 2009, 95(5):579-596
[4]Pierotti MA, Micheli A, Sutcliffe SB. The 3rd International Cancer Control Congress:international collaboration in an era of cancer as a global concern. Tumori 2009,95(5):565-567
[5]王启俊,祝伟星,邢秀梅,等。 北京城区女性乳腺癌发病死亡和生存情况20年监测分析.中国癌症杂志,2006,28(3)：46-51
[6]潘秀丹,王慧文,李洵,等。 沈阳市乳腺癌流行病学分析.现代预防医学杂志,2008,35(1)：52-55
[7]陈可欣,何敏,董淑芬,等。天津市女性乳腺癌发病率死亡率和生存率分析.中国癌症杂志,2002,24(6)：33-35
[8]Barnett CM. Survival data of patients with anthracycline-or taxane-pretreated or resistant metastatic breast cancer. Pharmacotherapy 2009,29(12):1482-1490
[9]Tsukuda K, Tsuji H, Kunitomo T, et al. Breast cancer with cartilaginous and/or osseous metaplasia diagnosed by lymph nodal metastasis:a case report. Acta Med Okayama 2009,63(6):367-371
[10]Ionta MT, Atzori F, Deidda MC, et al. Long-term outcomes in stage ⅢB breast cancer patients who achieved less than a pathological complete response ( [11]Bosco JL, Lash TL, Prout MN, et al.Breast cancer recurrence in older women five to ten years after diagnosis. Cancer Epidemiol Biomarkers Prev 2009, 18(11):2979-2983
[12]Barraclough DL, Platt-Higgins A, de Silva Rudland S, et al. The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients. Am JPathol 2009,175(5):1848-1857
[13]Dumitrescu RG, Cotarla I. Understanding breast cancer risk-where do we stand in 2005? J Cell Mol Med 2005,9(1):208-221
[14]Catanuto G, Patete P, Spano A, et al. New technologies for the assessment of breast surgical outcomes. Aesthet Surg J2009,29(6):505-508
[15]Bonanni B, Serrano D, Gandini S, et al. Randomized biomarker trial of anastrozole or low-dose tamoxifen or their combination in subjects with breast intraepithelial neoplasia. Clin Cancer Res 2009,15(22):7053-7060
[16]Stoeckelhuber BM, Noack F, Kapsimalakou S, et al. Radiofrequency ablation in breast tissue:experimental study for evaluation of radiofrequency effects in the bovine udder and review of the literature. J Vasc Interv Radiol 2009, 20(11):1477-1482
[17]Schwartz GF, Meltzer AJ, Lucarelli EA, et al. Breast conservation after neoadjuvant chemotherapy for stage II carcinoma of the breast. J Am Coll Surg 2005, 201(3):327-334
[18]Hussain-Hakimjee EA, Peng X, Mehta RR, et al. Growth inhibition of carcinogen-transformed MCF-12F breast epithelial cells and hormone-sensitive BT-474 breast cancer cells by 1alpha-hydroxyvitamin D5. Carcinogenesis 2006, 27(3):551-559
[19]Erol K, Baltali E, Altundag K, et al. Neoadjuvant chemotherapy with cyclophosphamide, mitoxantrone, and 5-fluorouracil in locally advanced breast cancer. Onkologie 2005,28(2):81-85
[20]Juranic ZD, Borojevic N, Jovanovic D, et al. Effects of X-ray irradiation on the overexpression of HER-2/Erb-B2 on breast cancer cell lines. JExp Clin Cancer Res 2004,23(4):675-680
[21]Somali I, Alacacioglu A, Tarhan MO, et al. Cisplatin plus gemcitabine chemotherapy in taxane/anthracycline-resistant metastatic breast cancer. Chemotherapy 2009,55(3):155-160
[22]Warm M, Kates R, Thomas A, et al. Side-effects of pre-operative epirubicin-paclitaxel therapy in primary breast cancer associated with tumor biology. Anticancer Res 2009,29(7):2675-2680
[23]Bergh J. Adjuvant chemotherapy for breast cancer-"one fits all"? Breast 2005, 14(6):564-569
[24]Dorr W, Bertmann S, Herrmann T. Radiation induced lung reactions in breast cancer therapy. Modulating factors and consequential effects. Strahlenther Onkol 2005, 181(9):567-573
[25]Howell A, Cuzick J. Vascular effects of aromatase inhibitors:data from clinical trials. J Steroid Biochem Mol Biol 2005,95(1-5):143-149
[26]Cheng YC, Rondon G, Sanchez LF, et al. Interleukin-2 and granulocyte-macrophage-colony-stimulating factor immunomodulation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer. Int J Hematol 2009,90(5):627-634
[27]Shih YC, Elting LS, Pavluck AL, et al. Immunotherapy in the initial treatment of newly diagnosed cancer patients:utilization trend and cost projections for non-Hodgkin's lymphoma, metastatic breast cancer, and metastatic colorectal cancer. Cancer Invest,28(1):46-53
[28]Hofmann MH, Heinrich J, Radziwil G, et al. A short hairpin DNA analogous to miR-125b inhibits C-Raf expression, proliferation, and survival of breast cancer cells. Mol Cancer Res 2009,7(10):1635-1644
[29]Rech AJ, Vonderheide RH. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci 2009,1174:99-106
[30]Nakajima S, Niizeki H, Tada M, et al. Trichostatin A with adenovirus-mediated p53 gene transfer synergistically induces apoptosis in breast cancer cell line MDA-MB-231. Oncol Rep 2009,22(1):143-148
[31]Desmedt C, Sperinde J, Piette F, et al. Quantitation of HER2 expression or HER2:HER2 dimers and differential survival in a cohort of metastatic breast cancer patients carefully selected for trastuzumab treatment primarily by FISH. Diagn Mol Pathol 2009,18(1):22-29
[32]Archer DF, Pinkerton JV, Utian WH, et al. Bazedoxifene, a selective estrogen receptor modulator:effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause 2009,16(6):1109-1115
[33]Yeon CH, Pegram MD. Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer. Invest New Drugs 2005,23(5):391-409
[34]Xie Z, Guo N, Yu M, et al. A new format of bispecific antibody:highly efficient heterodimerization, expression and tumor cell lysis. J Immunol Methods 2005, 296(1-2):95-101
[35]Boskovitz A, McLendon RE, Okamura T, et al. Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab. Nucl Med Biol 2009,36(6):659-669
[36]Alper O, Stetler-Stevenson WG, Harris LN, et al. Novel anti-filamin-A antibody detects a secreted variant of filamin-A in plasma from patients with breast carcinoma and high-grade astrocytoma. Cancer Sci 2009,100(9):1748-1756
[37]Leonard DS, Hill AD, Kelly L, et al. Anti-human epidermal growth factor receptor 2 monoclonal antibody therapy for breast cancer. Br J Surg 2002,89(3):262-271
[38]Chew I, Ng SB, Tan PH. Test and teach. Number fifty-three. Diagnosis:Spindle cell ductal carcinoma in situ with neuroendocrine differentiation. Pathology 2005, 37(1):76-79
[39]Tse GM, Tan PH, Moriya T. The role of immunohistochemistry in the differential diagnosis of papillary lesions of the breast. J Clin Pathol 2009,62(5):407-413
[40]Amiraslanov A, Muradov H, Velieva H. Breast endocrine cancer. Georgian Med News 2009(167):36-39
[41]Bonkhoff H, Fixemer T. [Neuroendocrine differentiation in prostate cancer:an unrecognized and therapy resistant phenotype]. Pathologe 2005,26(6):453-460
[42]Komiya A, Suzuki H, Imamoto T,et al. Neuroendocrine differentiation in the progression of prostate cancer. Int J Urol 2009,16(1):37-44
[43]Figueiredo KA, Palmer JB, Mui AL, Nelson CC, Cox ME:Demonstration of upregulated H2 relaxin mRNA expression during neuroendocrine differentiation of LNCaP prostate cancer cells and production of biologically active mammalian recombinant 6 histidine-tagged H2 relaxin. Ann N YAcad Sci 2005,1041:320-327
[44]Ather MH, Abbas F, Faruqui N, et al. Correlation of three immunohistochemically detected markers of neuroendocrine differentiation with clinical predictors of disease progression in prostate cancer. BMC Urol 2008,8:21
[45]Ham WS, Cho NH, Kim WT, et al. Pathological effects of prostate cancer correlate with neuroendocrine differentiation and PTEN expression after bicalutamide monotherapy. J Urol 2009,182(4):1378-1384
[46]Tawadros T, Martin D, Abderrahmani A, et al. IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation. Cell Signal 2005,17(8):929-939
[47]Chong JA, Tapia-Ramirez J, Kim S, et al. REST:a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 1995,80(6):949-957
[48]Schoenherr CJ, Anderson DJ. The neuron-restrictive silencer factor (NRSF):a coordinate repressor of multiple neuron-specific genes. Science 1995, 267(5202):1360-1363
[49]Bai G, Zhuang Z, Liu A, et al. The role of the RE1 element in activation of the NR1 promoter during neuronal differentiation. JNeurochem 2003,86(4):992-1005
[50]Bruce AW, Donaldson IJ, Wood IC, et al. Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proc Natl Acad Sci USA 2004,101(28):10458-10463
[51]Abrajano JJ, Qureshi IA, Gokhan S, et al. Differential deployment of REST and CoREST promotes glial subtype specification and oligodendrocyte lineage maturation. PLoS One 2009,4(11):e7665
[52]Andres ME, Burger C, Peral-Rubio MJ, et al. a functional corepressor required for regulation of neural-specific gene expression. Proc Natl Acad Sci U S A 1999, 96(17):9873-9878
[53]Grimes JA, Nielsen SJ, Battaglioli E, et al. The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex. J Biol Chem 2000, 275(13):9461-9467
[54]Kim MY, Jeong BC, Lee JH, et al. A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells. Proc Natl Acad Sci U S A 2006,103(35):13074-13079.
[55]Albert PR, Lemonde S:5-HT1A receptors, gene repression, and depression:guilt by association. Neuroscientist 2004,10(6):575-593
[56]Bergsland M, Werme M, Malewicz M, et al. The establishment of neuronal properties is controlled by Sox4 and Sox1l. Genes Dev 2006,20(24):3475-3486
[57]Wood IC, Roopra A, Buckley NJ. Neural specific expression of the m4 muscaririic acetylcholine receptor gene is mediated by a RE1/NRSE-type silencing element. J Biol Chem 1996,271(24):14221-14225
[58]Abrajano JJ, Qureshi IA, Gokhan S, et al. REST and CoREST modulate neuronal subtype specification, maturation and maintenance. PLoS One 2009,4(12):e7936
[59]D'Alessandro R, Klajn A, Stucchi L,et al. Expression of the neurosecretory process in PC12 cells is governed by REST. JNeurochem 2008,105(4):1369-1383
[60]Lorincz MT, Detloff PJ, Albin RL, et al. Embryonic stem cells expressing expanded CAG repeats undergo aberrant neuronal differentiation and have persistent Oct-4 and REST/NRSF expression. Mol Cell Neurosci 2004,26(1):135-143
[61]Su X, Kameoka S, Lentz S, et al. Activation of REST/NRSF target genes in neural stem cells is sufficient to cause neuronal differentiation. Mol Cell Biol 2004, 24(18):8018-8025
[62]Guardavaccaro D, Frescas D, Dorrello NV, et al. Control of chromosome stability by the beta-TrCP-REST-Mad2 axis. Nature 2008,452(7185):365-369
[63]Westbrook TF, Martin ES, Schlabach MR, et al. A genetic screen for candidate tumor suppressors identifies REST. Cell 2005,121(6):837-848.
[64]Coulson JM. Transcriptional regulation:cancer, neurons and the REST. Curr Biol 2005,15(17):R665-668
[65]Ariano P, Zamburlin P, D'Alessandro R, et al. Differential repression by the transcription factor REST/NRSF of the various Ca(2+) signalling mechanisms in pheochromocytoma PC12 cells. Cell Calcium.2010,47 (4):360-368
[66]Blom T, Tynninen 0, Puputti M, et al. Molecular genetic analysis of the REST/NRSF gene in nervous system tumors. Acta Neuropathol 2006, 112(4):483-490
[67]Shai A, Pitot HC, Lambert PF. p53 Loss synergizes with estrogen and papillomaviral oncogenes to induce cervical and breast cancers. Cancer Res 2008, 68(8):2622-2631
[68]Chen Y, Olopade OI. MYC in breast tumor progression. Expert Rev Anticancer Ther 2008,8(10):1689-1698
[69]Hagen AI, Bofin AM, Ytterhus B, et al. Amplification of TOP2A and HER-2 genes in breast cancers occurring in patients harbouring BRCA1 germline mutations. Acta Oncol 2007,46(2):199-203
[70]Ozer E, Sis B, Ozen E, et al. BRCA1, C-erbB-2, and H-ras gene expressions in young women with breast cancer. An immunohistochemical study. Appl Immunohistochem Mol Morphol 2000,8(1):12-18
[71]Nagai H, Harada H, Emi M. [Oncogene and tumor suppressor gene]. Nippon Rinsho 2000,58 Suppl:25-29
[72]Qureshi IA, Mehler MF. Regulation of non-coding RNA networks in the nervous system-what's the REST of the story? Neurosci Lett 2009,466(2):73-80
[73]Donahue LM, Reinhart AJ. POU domain genes are differentially expressed in the early stages after lineage commitment of the PNS-derived stem cell line, RT4-AC. Brain Res Dev Brain Res 1998,106(1-2):1-12
[74]Das C, Gadad SS, Kundu TK. Human positive coactivator 4 controls heterochromatinization and silencing of neural gene expression by interacting with REST/NRSF and CoREST. J Mol Biol,397(1):1-12
[75]Lee JH, Chai YG, Hersh LB. Expression patterns of mouse repressor element-1 silencing transcription factor 4 (REST4) and its possible function in neuroblastoma. J Mol Neurosci 2000,15(3):205-214
[76]Lee JH, Shimojo M, Chai YG, et al. Studies on the interaction of REST4 with the cholinergic repressor element-1/neuron restrictive silencer element. Brain Res Mol Brain Res 2000,80(1):88-98
[77]Shimojo M, Hersh LB. REST/NRSF-interacting LIM domain protein, a putative nuclear translocation receptor. Mol Cell Biol 2003,23(24):9025-9031
[78]Shimojo M. Characterization of the nuclear targeting signal of REST/NRSF. Neurosci Lett 2006,398(3):161-166
[79]Tabuchi A, Yamada T, Sasagawa S, et al. REST4-mediated modulation of REST/NRSF-silencing function during BDNF gene promoter activation. Biochem Biophys Res Commun 2002,290(1):415-420
[80]Kuwabara T, Hsieh J, Nakashima K, et al. A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 2004,116(6):779-793
[81]Westbrook TF, Hu G, Ang XL, et al. SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 2008, 452(7185):370-374
[82]Tang W, Li Y, Yu D, et al. Targeting beta-transducin repeat-containing protein E3 ubiquitin ligase augments the effects of antitumor drugs on breast cancer cells. Cancer Res 2005,65(5):1904-1908
[83]Li Y, Clevenger CV, Minkovsky N, et al. Stabilization of prolactin receptor in breast cancer cells. Oncogene 2006,25(13):1896-1902
[84]Plotnikov A, Li Y, Tran TH, et al. Oncogene-mediated inhibition of glycogen synthase kinase 3 beta impairs degradation of prolactin receptor. Cancer Res 2008, 68(5):1354-1361
[85]Zhou BP, Deng J, Xia W, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004, 6(10):931-940
[86]Christensen WN, Strong EW, Bains MS, et al. Neuroendocrine differentiation in the glandular peripheral nerve sheath tumor. Pathologic distinction from the biphasic synovial sarcoma with glands. Am JSurg Pathol 1988,12(6):417-426
[87]Ishida E, Nakamura M, Shimada K, et al. Immunohistochemical analysis of neuroendocrine differentiation in prostate cancer. Pathobiology 2009,76(1):30-38
[88]Jones FS, Meech R. Knockout of REST/NRSF shows that the protein is a potent repressor of neuronally expressed genes in non-neural tissues. Bioessays 1999, 21(5):372-376
[89]Graeser M, Bosse K, Brosig M, et al. Association of hormone receptor status with grading, age of onset, and tumor size in BRCA1-associated breast cancer. Virchows Arch 2009,454(5):519-524
[90]Carnevale RP, Proietti CJ, Salatino M, et al. Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways. Mol Endocrinol 2007,21(6):1335-1358
[91]Anderson E. The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res 2002,4(5):197-201
[92]Murphy LC, Watson P. Steroid receptors in human breast tumorigenesis and breast cancer progression. Biomed Pharmacother 2002,56(2):65-77
[93]Ernberg IT. Oncogenes and tumor growth factors in breast cancer. A minireview. Acta Oncol 1990,29(3):331-334
[94]Brown RE. HER-2/neu-Positive breast carcinoma:molecular concomitants by proteomic analysis and their therapeutic implications. Ann Clin Lab Sci 2002, 32(1):12-21
[95]Cao W, Zhang B, Liu Y, et al. High-level SLP-2 expression and HER-2/neu protein expression are associated with decreased breast cancer patient survival. Am J Clin Pathol 2007,128(3):430-436
[96]Sekine I, Shimizu C, Nishio K, et al. A literature review of molecular markers predictive of clinical response to cytotoxic chemotherapy in patients with breast cancer. Int J Clin Oncol 2009,14(2):112-119
[97]Azizun N, Bhurgri Y, Raza F,et al. Comparison of ER, PR and HER-2/neu (C-erb B 2) reactivity pattern with histologic grade, tumor size and lymph node status in breast cancer. Asian Pac J Cancer Prev 2008,9(4):553-556
[98]Hussein MR, Abd-Elwahed SR, Abdulwahed AR. Alterations of estrogen receptors, progesterone receptors and c-erbB2 oncogene protein expression in ductal carcinomas of the breast. Cell Biol Int 2008,32(6):698-707
[99]Faratian D, Kay C, Robson T, et al. Automated image analysis for high-throughput quantitative detection of ER and PR expression levels in large-scale clinical studies: the TEAM Trial Experience. Histopathology 2009,55(5):587-593
[100]Parise CA, Bauer KR, Brown MM, et al. Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California,1999-2004. Breast J 2009,15(6):593-602
[101]Elsberger B, Tan BA, Mitchell TJ, et al. Is expression or activation of Src kinase associated with cancer-specific survival in ER-, PR-and HER2-negative breast cancer patients? Am J Pathol 2009,175(4):1389-1397
[102]Fernandes RC, Bevilacqua JL, Soares IC, et al. Coordinated expression of ER, PR and HER2 define different prognostic subtypes among poorly differentiated breast carcinomas. Histopathology 2009,55(3):346-352
[103]Wu J, Xie X. Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome Biol 2006,7(9):R85
[104]Zuccato C, Belyaev N, Conforti P, et al. Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington's disease. JNeurosci 2007,27(26):6972-6983
[105]Barrachina M, Moreno J, Juves S, et al. Target genes of neuron-restrictive silencer factor are abnormally up-regulated in human myotilinopathy. Am J Pathol 2007, 171(4):1312-1323
[106]Armisen R, Fuentes R, Olguin P, et al. Repressor element-1 silencing transcription/neuron-restrictive silencer factor is required for neural sodium channel expression during development of Xenopus. JNeurosci 2002,22(19):8347-8351
[107]Eggen BJ, Mandel G. Regulation of sodium channel gene expression by transcriptional silencing. Dev Neurosci 1997,19(1):25-26
[108]Garcia-Sanchez R, Ayala-Lujan J, Hernandez-Perez A, et al. Identification of repressor element 1 in cytochrome P450 genes and their negative regulation by RE1 silencing transcription factor/neuron-restrictive silencer factor. Biochim Biophys Acta 2003,1620(1-3):39-46
[109]Kallunki P, Edelman GM, Jones FS. Tissue-specific expression of the L1 cell adhesion molecule is modulated by the neural restrictive silencer element. J Cell Biol 1997,138(6):1343-1354
[110]Otto SJ, McCorkle SR, Hover J, et al. A new binding motif for the transcriptional repressor REST uncovers large gene networks devoted to neuronal functions. J Neurosci 2007,27(25):6729-6739
[111]Schoenherr CJ, Paquette AJ, Anderson DJ. Identification of potential target genes for the neuron-restrictive silencer factor. Proc Natl Acad Sci U S A 1996, 93(18):9881-9886
[112]Gillies S, Haddley K, Vasiliou S, et al. The human neurokinin B gene, TAC3, and its promoter are regulated by Neuron Restrictive Silencing Factor (NRSF) transcription factor family. Neuropeptides 2009,43(4):333-340
[113]Greco SJ, Smirnov SV, Murthy RG, et al. Synergy between the RE-1 silencer of transcription and NFkappaB in the repression of the neurotransmitter gene TAC1 in human mesenchymal stem cells. J Biol Chem 2007,282(41):30039-30050
[114]Lonnerberg P, Schoenherr CJ, Anderson DJ, et al. Cell type-specific regulation of choline acetyltransferase gene expression. Role of the neuron-restrictive silencer element and cholinergic-specific enhancer sequences. J Biol Chem 1996, 271(52):33358-33365
[115]Weissman AM. How much REST is enough? Cancer Cell 2008,13(5):381-383.
[116]Moss AC, Jacobson GM, Walker LE, et al. SCG3 transcript in peripheral blood is a prognostic biomarker for REST-deficient small cell lung cancer. Clin Cancer Res 2009,15(1):274-283
[117]Reddy BY, Greco SJ, Patel PS, et al. RE-1-silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells. Proc Natl Acad Sci U S A 2009,106(11):4408-4413
[118]Hannon GJ, Conklin DS. RNA interference by short hairpin RNAs expressed in vertebrate cells. Methods Mol Biol 2004,257:255-266
[119]Aravin AA, Vagin VV, Naumova NM, et al. [The phenomenon of RNA interference and development of organism]. Ontogenez 2002,33(5):349-360
[120]Harborth J, Elbashir SM, Bechert K, et al. Identification of essential genes in cultured mammalian cells using small interfering RNAs. J Cell Sci 2001,114(Pt 24):4557-4565
[121]Kumar R, Adams B, Oldenburg A, et al. Characterisation and expression of a PP1 serine/threonine protein phosphatase (PfPP1) from the malaria parasite, Plasmodium falciparum:demonstration of its essential role using RNA interference. Malar J 2002,1-5
[122]Mukherjea D, Jajoo S, Whitworth C, et al. Short interfering RNA against transient receptor potential vanilloid 1 attenuates cisplatin-induced hearing loss in the rat. J Neurosci 2008,28(49):13056-13065
[123]Montgomery MK, Xu S, Fire A. RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans. Proc Natl Acad Sci U S A 1998, 95(26):15502-15507
[124]Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998,391(6669):806-811
[125]Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21-and 22-nucleotide RNAs. Genes Dev 2001,15(2):188-200
[126]Bric A, Miething C, Bialucha CU, et al. Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model. Cancer Cell 2009,16(4):324-335
[127]Cerutti H. RNA interference:traveling in the cell and gaining functions? Trends Genet 2003,19(1):39-46
[128]Hamada M, Ohtsuka T, Kawaida R, et al. Effects on RNA interference in gene expression (RNAi) in cultured mammalian cells of mismatches and the introduction of chemical modifications at the 3'-ends of siRNAs. Antisense Nucleic Acid Drug Dev 2002,12(5):301-309
[129]Golding MC, Long CR, Carmell MA, et al. Suppression of prion protein in livestock by RNA interference. Proc Natl Acad Sci U S A 2006,103(14):5285-5290
[130]Gupta S, Schoer RA, Egan JE, et al. Inducible, reversible, and stable RNA interference in mammalian cells. Proc Natl Acad Sci USA 2004,101(7):1927-1932
[131]Borkhardt A. Blocking oncogenes in malignant cells by RNA interference-new hope for a highly specific cancer treatment? Cancer Cell 2002,2(3):167-168
[132]Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002,2(3):243-247
[133]Martinez MA, Clotet B, Este JA. RNA interference of HIV replication. Trends Immunol 2002,23(12):559-561
[134]Martinez MA, Gutierrez A, Armand-Ugon M, et al. Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication. AIDS 2002,16(18):2385-2390
[135]Saksela K. [RNA interference in the prevention of viral diseases?]. Duodecim 2002, 118(21):2191-2198
[136]Silva JM, Hammond SM, Hannon GJ. RNA interference:a promising approach to antiviral therapy? Trends Mol Med 2002,8(11):505-508
[137]Haiman CA, Stram DO, Cheng I, et al. Common genetic variation at PTEN and risk of sporadic breast and prostate cancer. Cancer Epidemiol Biomarkers Prev 2006, 15(5):1021-1025
[138]McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 2006,46:249-279
[139]Weng LP, Brown JL, Baker KM, et al. PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Hum Mol Genet 2002,11(15):1687-1696
[140]Yu Y, Feig LA. Involvement of R-Ras and Ral GTPases in estrogen-independent proliferation of breast cancer cells. Oncogene 2002,21(49):7557-7568
[141]Shin I, Kim S, Song H, et al. H-Ras-specific activation of Rac-MKK3/6-p38
pathway:its critical role in invasion and migration of breast epithelial cells. J Biol Chem 2005,280(15):14675-14683
[142]Jones RA, Campbell CI, Gunther EJ, et al. Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene 2007,26(11):1636-1644
[143]Lee AV, Taylor ST, Greenall J, et al. Rapid induction of IGF-IR signaling in normal and tumor tissue following intravenous injection of IGF-I in mice. Horm Metab Res 2003,35(11-12):651-655
[144]Schaefer JS, Zhang M. Role of maspin in tumor metastasis and angiogenesis. Curr Mol Med 2003,3(7):653-658
[145]Streuli CH. Maspin is a tumour suppressor that inhibits breast cancer tumour metastasis in vivo. Breast Cancer Res 2002,4(4):137-140
[146]Xiong LJ, Liang CH, Deng HY. [Relevant factors of nm23 protein expression and dangerous factors of bone metastasis in breast cancer]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2004,29(1):75-78
[147]Wu M, Wu ZF, Kumar-Sinha C, et al. RhoC induces differential expression of genes involved in invasion and metastasis in MCF10A breast cells. Breast Cancer Res Treat 2004,84(1):3-12
[148]Huber MA, Azoitei N, Baumann B, et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004,114(4):569-581
[149]Shiomi T, Okada Y. MT1-MMP and MMP-7 in invasion and metastasis of human cancers. Cancer Metastasis Rev 2003,22(2-3):145-152
[150]Wang FM, Liu HQ, Liu SR, et al. SHP-2 promoting migration and metastasis of MCF-7 with loss of E-cadherin, dephosphorylation of FAK and secretion of MMP-9 induced by IL-lbeta in vivo and in vitro. Breast Cancer Res Treat 2005,89(1):5-14
[151]Wang X, Nagase H, Watanabe T, et al. Inhibition of MMP-9 transcription and suppression of tumor metastasis by pyrrole-imidazole polyamide. Cancer Sci 2010, 101(3):759-66
[152]Hao L, Zhang C, Qiu Y, et al. Recombination of CXCR4, VEGF, and MMP-9 predicting lymph node metastasis in human breast cancer. Cancer Lett 2007, 253(1):34-42
[153]Suarez-Cuervo C, Merrell MA, Watson L, et al. Breast cancer cells with inhibition of p38alpha have decreased MMP-9 activity and exhibit decreased bone metastasis in mice. Clin Exp Metastasis 2004,21(6):525-533
[154]Liu Z, Liu M, Niu G, et al. Genome-wide identification of target genes repressed by the zinc finger transcription factor REST/NRSF in the HEK 293 cell line. Acta Biochim Biophys Sin (Shanghai) 2009,41(12):1008-1017 的研究结果发现肿瘤分级越高,生存率越低;分级低者NE细胞更常见,但NE细胞阳性和阴性的肿瘤,5年生存率均无差异,认为NED程度对前列腺癌的预后无实际价值。同样,卵巢上皮性肿瘤的研究中发现,神经内分泌分化的出现可能与患者不良预后有关[33]。然而,在乳腺癌伴神经内分泌分化的研究中,有学者称伴神经内分泌分化的乳腺癌预后较好,也有研究显示其与预后无相关性。故神经内分泌分化的出现与预后的关系值得进一步的探索与研究。5、结语
通过上述的分析与研究,我们不难看出,恶性肿瘤细胞出现神经内分泌分化现象对于肿瘤本身的发生与发展,及对肿瘤的预后均有着较为重要的影响。而且,研究表明,在不同的肿瘤中,神经内分泌分化的出现会产生截然不同的效果。如在前列腺癌的研究中,大部分的研究显示伴神经内分泌分化的肿瘤治疗效果差,预后不好；卵巢上皮性肿瘤中出现的NE细胞可以使其周围细胞的抗凋亡能力增强,有利于肿瘤的侵袭与转移；而伴神经内分泌分化的非小细胞肺癌对化疗的敏感性增强；乳腺癌中有报道称,伴神经内分泌分化与肿瘤预后无关甚至有较好的预后。这些看似矛盾的现象需要医学工作者辨证地对待,深入研究神经内分泌分化这一现象出现的原因与意义。
[1]Tavassoli Fa, Devilee P. World Health Orgnization classification of tumors pathology & genetics, tumors of the breast and female genital organs. Lyon:IACR Press,2003,32-36
[2]Shaoul R, Hong D, Okada Y, Cutz E, Marcon MA. Lineage development in a patient without goblet, paneth, and enteroendocrine cells:a clue for intestinal epithelial differentiation. Pediatr Res.2005;58(3):492-498
[3]Kim J, Adam RM, Freeman MR. Activation of the Erk mitogen-activated protein kinase pathway stimulates neuroendocrine differentiation in LNCaP cells independently of cell cycle withdrawal and STAT3 phosphorylation. Cancer Res.2002,62(5):1549-1554
[4]Horiatis D, Wang Q, Pinski J. A new screening system for proliferation-independent anti-cancer agents. Cancer Lett.2004,210(1):119-124
[5]Pinski J, Wang Q, Quek ML, et al. Genistein-induced neuroendocrine differentiation of prostate cancer cells. Prostate.2006,66(11): 1136-1143
[6]Schalken JA, van Leenders G. Cellular and molecular biology of the prostate:stem cell biology. Urology.2003;62(5 Suppl 1):11-20
[7]Bajetta E, Ferrari L, Martinetti A, et al. Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer,1999,86 (5): 858-865
[8]Jongsma J, Oomen MH, Noordzij MA, et al. Androgen deprivation of the PC-310 [correction of prohormone convertase-310] human prostate cancer model system induces neuroendocrine differentiation. Cancer Res. 2000;60(3):741-748
[9]Jiborn T, Abrahamson M, Gadaleanu V, et al. Aberrant expression of cystatin C in prostate cancer is associated with neuroendocrine differentiation. BJU Int.2006;98(1):189-196
[10]Figueiredo KA, Palmer JB, Cox ME, et al. Demonstration of upregulated H2 relaxin mRNA expression during neuroendocrine differentiation of LNCaP prostate cancer cells and production of biologically active mammalian recombinant 6 histidine-tagged H2 relaxin. Ann N Y Acad Sci. 2005:1041:320-327
[11]Iyoda A, Hiroshima K, Toyozaki T et al. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer 2001; 91(11):1992-2000
[12]Kimura H, Yamaguchi T, Nishino K, et al. Clinical significance of serum neuronspecific enlase on non-small cell lung cancer. Nihon Kokyuk Gakkai Zasshi,1998:36128-32
[13]Satoh H, Ishikawa H, Kurishima K, et al. Cut-off levels of NSE to differentiate SCLC from NSCLC. J Oncol Rep,2002; 9(3):581-3
[14]欧阳能太,陈国勤,钟南山等.非小细胞肺癌神经内分泌表达的检测及临床意义。中华结核和呼吸杂志.2001,24：90-92
[15]Di Sant'Agnese PA. Neuroendocrine differentiation in carcinoma of the prostate. Diagnostic, prognostic, and therapeutic implications. Cancer, 1992,70:254-268
[16]DiSant'Agnese PA. Neuroendocrine differentiation in carcinoma of the prostate:diagnostic, prognostic, and therapeutic implications. Cancer. 1993,70:254-268
[17]Vashchenko N, Abrahamsson PA. Neuroendocrine differentiation in prostate cancer:implications for new treatment modalities. Eur Urol.2005, 47(2):147-155
[18]Nakada SY, diSant'Agnese PA, Moynes RA et al. The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. Cancer Research.1933,53:1967-1970
[19].Hansson J, Abrahamsson PA. Neuroendocrine differentiation in prostatic carcinoma. Scand J Urol Nephrol Suppl.2003, (212):28-36
[20]Lepidi H, Monges G, Delpero JR, et al. Gastric adenocarcinoma with an endocrine component. Report of nine cases. Ann Pathol,1993,13 (1): 17-22
[21]Waldum HL, Aase S, Kvetnoi I, et al. Neuroendocrine differentiation in human gastric carcinoma. Cancer,1998,83 (3):435-443
[22]Luisa GM, Achille P. Carciond tumors:review of a single institution experience. Ann oncol,2000,11(2):58-63
[23]Lapertosa G. Histogenetic considerations on mucinous cystomas of the ovary based on histochemical and immunohistochemical findings. Pathologica,1989,81(1074):381-401
[24]Lin M, Hanai J, Wada A, et al. Argyrophilia in ovarian serous tumors. A comparative study in 127 epithelial ovarian tumors. Histol Histopathol,1991,6(4):477-484
[25]Turitto G, Frattolillo A, Iodice P, et al. Neuroendocrine features of prostatic tumors:state of the art. Recenti Prog Med,2003,94(12): 568-572
[26]Furlan D, Cerutti R, Uccella S, et al. Different molecular p rofiles characterize well2differentiated endocrine tumors and poorly differentiated endocrine carcinomas of the gastroentero pancreatic tract. Clin Cancer Res,2004,10 (3):947-957
[27]Segal N, Cohen R, Haffejee Z, et al. BCL-2 proto-onocogene expression in prostate cancer and its relationship to the prostate neuroendocrine cell. Arch Pathol Lab Med,1994,118:616-618
[28]Ruff in IE, Bongiovann IM, Cavallo A, et al. The significance of associated p re-invasive lesions in patients resected for primary lung neop lasms. Eur J Cardiothorac Surg,2004,26(1):165-172
[29]Adwer KL; Ppel G. Neuroendokrine Tumoren des Gastrointestinaltrakts. Pathologe,2003,24 (4):287-296
[30]Tanaka M, Suzuki Y. Progression of p rostate cancer to neuroendocrine cell tumor. Inter J Urol,2001,8 (8):431-436
[31]Cohen R, Glezereson G, Haffejee Z. Neuroendocrine cells:a new prognostic parameter in prostate cancer. Br J Urol,1991,58:258-262
[32]Allen FJ, Van Velden DJ, Heyns CF. Are neuroendocrine cells of practical value as an independent prognostic parameter in prostate cancer. Br J Urol,1995,75(6):751-754
[33]蒋立艳,王自能,路妍妍,等。卵巢上皮性肿瘤神经内分泌分化及其意义。广东医学2007；28(2)：248-251
[2]Knaul F, Bustreo F, Ha E, et al. Breast cancer:why link early detection to reproductive health interventions in developing countries? Salud Publica Mex 2009, 51 Suppl2:s220-227
[3]Micheli A, Sanz N, Mwangi-Powell F, et al. International collaborations in cancer control and the Third International Cancer Control Congress. Tumori 2009, 95(5):579-596
[4]Pierotti MA, Micheli A, Sutcliffe SB. The 3rd International Cancer Control Congress:international collaboration in an era of cancer as a global concern. Tumori 2009,95(5):565-567
[5]王启俊,祝伟星,邢秀梅,等。 北京城区女性乳腺癌发病死亡和生存情况20年监测分析.中国癌症杂志,2006,28(3)：46-51
[6]潘秀丹,王慧文,李洵,等。 沈阳市乳腺癌流行病学分析.现代预防医学杂志,2008,35(1)：52-55
[7]陈可欣,何敏,董淑芬,等。天津市女性乳腺癌发病率死亡率和生存率分析.中国癌症杂志,2002,24(6)：33-35
[8]Barnett CM. Survival data of patients with anthracycline-or taxane-pretreated or resistant metastatic breast cancer. Pharmacotherapy 2009,29(12):1482-1490
[9]Tsukuda K, Tsuji H, Kunitomo T, et al. Breast cancer with cartilaginous and/or osseous metaplasia diagnosed by lymph nodal metastasis:a case report. Acta Med Okayama 2009,63(6):367-371
[10]Ionta MT, Atzori F, Deidda MC, et al. Long-term outcomes in stage ⅢB breast cancer patients who achieved less than a pathological complete response (
[12]Barraclough DL, Platt-Higgins A, de Silva Rudland S, et al. The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients. Am JPathol 2009,175(5):1848-1857
[13]Dumitrescu RG, Cotarla I. Understanding breast cancer risk-where do we stand in 2005? J Cell Mol Med 2005,9(1):208-221
[14]Catanuto G, Patete P, Spano A, et al. New technologies for the assessment of breast surgical outcomes. Aesthet Surg J2009,29(6):505-508
[15]Bonanni B, Serrano D, Gandini S, et al. Randomized biomarker trial of anastrozole or low-dose tamoxifen or their combination in subjects with breast intraepithelial neoplasia. Clin Cancer Res 2009,15(22):7053-7060
[16]Stoeckelhuber BM, Noack F, Kapsimalakou S, et al. Radiofrequency ablation in breast tissue:experimental study for evaluation of radiofrequency effects in the bovine udder and review of the literature. J Vasc Interv Radiol 2009, 20(11):1477-1482
[17]Schwartz GF, Meltzer AJ, Lucarelli EA, et al. Breast conservation after neoadjuvant chemotherapy for stage II carcinoma of the breast. J Am Coll Surg 2005, 201(3):327-334
[18]Hussain-Hakimjee EA, Peng X, Mehta RR, et al. Growth inhibition of carcinogen-transformed MCF-12F breast epithelial cells and hormone-sensitive BT-474 breast cancer cells by 1alpha-hydroxyvitamin D5. Carcinogenesis 2006, 27(3):551-559
[19]Erol K, Baltali E, Altundag K, et al. Neoadjuvant chemotherapy with cyclophosphamide, mitoxantrone, and 5-fluorouracil in locally advanced breast cancer. Onkologie 2005,28(2):81-85
[20]Juranic ZD, Borojevic N, Jovanovic D, et al. Effects of X-ray irradiation on the overexpression of HER-2/Erb-B2 on breast cancer cell lines. JExp Clin Cancer Res 2004,23(4):675-680
[21]Somali I, Alacacioglu A, Tarhan MO, et al. Cisplatin plus gemcitabine chemotherapy in taxane/anthracycline-resistant metastatic breast cancer. Chemotherapy 2009,55(3):155-160
[22]Warm M, Kates R, Thomas A, et al. Side-effects of pre-operative epirubicin-paclitaxel therapy in primary breast cancer associated with tumor biology. Anticancer Res 2009,29(7):2675-2680
[23]Bergh J. Adjuvant chemotherapy for breast cancer-"one fits all"? Breast 2005, 14(6):564-569
[24]Dorr W, Bertmann S, Herrmann T. Radiation induced lung reactions in breast cancer therapy. Modulating factors and consequential effects. Strahlenther Onkol 2005, 181(9):567-573
[25]Howell A, Cuzick J. Vascular effects of aromatase inhibitors:data from clinical trials. J Steroid Biochem Mol Biol 2005,95(1-5):143-149
[26]Cheng YC, Rondon G, Sanchez LF, et al. Interleukin-2 and granulocyte-macrophage-colony-stimulating factor immunomodulation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with metastatic breast cancer. Int J Hematol 2009,90(5):627-634
[27]Shih YC, Elting LS, Pavluck AL, et al. Immunotherapy in the initial treatment of newly diagnosed cancer patients:utilization trend and cost projections for non-Hodgkin's lymphoma, metastatic breast cancer, and metastatic colorectal cancer. Cancer Invest,28(1):46-53
[28]Hofmann MH, Heinrich J, Radziwil G, et al. A short hairpin DNA analogous to miR-125b inhibits C-Raf expression, proliferation, and survival of breast cancer cells. Mol Cancer Res 2009,7(10):1635-1644
[29]Rech AJ, Vonderheide RH. Clinical use of anti-CD25 antibody daclizumab to enhance immune responses to tumor antigen vaccination by targeting regulatory T cells. Ann N Y Acad Sci 2009,1174:99-106
[30]Nakajima S, Niizeki H, Tada M, et al. Trichostatin A with adenovirus-mediated p53 gene transfer synergistically induces apoptosis in breast cancer cell line MDA-MB-231. Oncol Rep 2009,22(1):143-148
[31]Desmedt C, Sperinde J, Piette F, et al. Quantitation of HER2 expression or HER2:HER2 dimers and differential survival in a cohort of metastatic breast cancer patients carefully selected for trastuzumab treatment primarily by FISH. Diagn Mol Pathol 2009,18(1):22-29
[32]Archer DF, Pinkerton JV, Utian WH, et al. Bazedoxifene, a selective estrogen receptor modulator:effects on the endometrium, ovaries, and breast from a randomized controlled trial in osteoporotic postmenopausal women. Menopause 2009,16(6):1109-1115
[33]Yeon CH, Pegram MD. Anti-erbB-2 antibody trastuzumab in the treatment of HER2-amplified breast cancer. Invest New Drugs 2005,23(5):391-409
[34]Xie Z, Guo N, Yu M, et al. A new format of bispecific antibody:highly efficient heterodimerization, expression and tumor cell lysis. J Immunol Methods 2005, 296(1-2):95-101
[35]Boskovitz A, McLendon RE, Okamura T, et al. Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab. Nucl Med Biol 2009,36(6):659-669
[36]Alper O, Stetler-Stevenson WG, Harris LN, et al. Novel anti-filamin-A antibody detects a secreted variant of filamin-A in plasma from patients with breast carcinoma and high-grade astrocytoma. Cancer Sci 2009,100(9):1748-1756
[37]Leonard DS, Hill AD, Kelly L, et al. Anti-human epidermal growth factor receptor 2 monoclonal antibody therapy for breast cancer. Br J Surg 2002,89(3):262-271
[38]Chew I, Ng SB, Tan PH. Test and teach. Number fifty-three. Diagnosis:Spindle cell ductal carcinoma in situ with neuroendocrine differentiation. Pathology 2005, 37(1):76-79
[39]Tse GM, Tan PH, Moriya T. The role of immunohistochemistry in the differential diagnosis of papillary lesions of the breast. J Clin Pathol 2009,62(5):407-413
[40]Amiraslanov A, Muradov H, Velieva H. Breast endocrine cancer. Georgian Med News 2009(167):36-39
[41]Bonkhoff H, Fixemer T. [Neuroendocrine differentiation in prostate cancer:an unrecognized and therapy resistant phenotype]. Pathologe 2005,26(6):453-460
[42]Komiya A, Suzuki H, Imamoto T,et al. Neuroendocrine differentiation in the progression of prostate cancer. Int J Urol 2009,16(1):37-44
[43]Figueiredo KA, Palmer JB, Mui AL, Nelson CC, Cox ME:Demonstration of upregulated H2 relaxin mRNA expression during neuroendocrine differentiation of LNCaP prostate cancer cells and production of biologically active mammalian recombinant 6 histidine-tagged H2 relaxin. Ann N YAcad Sci 2005,1041:320-327
[44]Ather MH, Abbas F, Faruqui N, et al. Correlation of three immunohistochemically detected markers of neuroendocrine differentiation with clinical predictors of disease progression in prostate cancer. BMC Urol 2008,8:21
[45]Ham WS, Cho NH, Kim WT, et al. Pathological effects of prostate cancer correlate with neuroendocrine differentiation and PTEN expression after bicalutamide monotherapy. J Urol 2009,182(4):1378-1384
[46]Tawadros T, Martin D, Abderrahmani A, et al. IB1/JIP-1 controls JNK activation and increased during prostatic LNCaP cells neuroendocrine differentiation. Cell Signal 2005,17(8):929-939
[47]Chong JA, Tapia-Ramirez J, Kim S, et al. REST:a mammalian silencer protein that restricts sodium channel gene expression to neurons. Cell 1995,80(6):949-957
[48]Schoenherr CJ, Anderson DJ. The neuron-restrictive silencer factor (NRSF):a coordinate repressor of multiple neuron-specific genes. Science 1995, 267(5202):1360-1363
[49]Bai G, Zhuang Z, Liu A, et al. The role of the RE1 element in activation of the NR1 promoter during neuronal differentiation. JNeurochem 2003,86(4):992-1005
[50]Bruce AW, Donaldson IJ, Wood IC, et al. Genome-wide analysis of repressor element 1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) target genes. Proc Natl Acad Sci USA 2004,101(28):10458-10463
[51]Abrajano JJ, Qureshi IA, Gokhan S, et al. Differential deployment of REST and CoREST promotes glial subtype specification and oligodendrocyte lineage maturation. PLoS One 2009,4(11):e7665
[52]Andres ME, Burger C, Peral-Rubio MJ, et al. a functional corepressor required for regulation of neural-specific gene expression. Proc Natl Acad Sci U S A 1999, 96(17):9873-9878
[53]Grimes JA, Nielsen SJ, Battaglioli E, et al. The co-repressor mSin3A is a functional component of the REST-CoREST repressor complex. J Biol Chem 2000, 275(13):9461-9467
[54]Kim MY, Jeong BC, Lee JH, et al. A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells. Proc Natl Acad Sci U S A 2006,103(35):13074-13079.
[55]Albert PR, Lemonde S:5-HT1A receptors, gene repression, and depression:guilt by association. Neuroscientist 2004,10(6):575-593
[56]Bergsland M, Werme M, Malewicz M, et al. The establishment of neuronal properties is controlled by Sox4 and Sox1l. Genes Dev 2006,20(24):3475-3486
[57]Wood IC, Roopra A, Buckley NJ. Neural specific expression of the m4 muscaririic acetylcholine receptor gene is mediated by a RE1/NRSE-type silencing element. J Biol Chem 1996,271(24):14221-14225
[58]Abrajano JJ, Qureshi IA, Gokhan S, et al. REST and CoREST modulate neuronal subtype specification, maturation and maintenance. PLoS One 2009,4(12):e7936
[59]D'Alessandro R, Klajn A, Stucchi L,et al. Expression of the neurosecretory process in PC12 cells is governed by REST. JNeurochem 2008,105(4):1369-1383
[60]Lorincz MT, Detloff PJ, Albin RL, et al. Embryonic stem cells expressing expanded CAG repeats undergo aberrant neuronal differentiation and have persistent Oct-4 and REST/NRSF expression. Mol Cell Neurosci 2004,26(1):135-143
[61]Su X, Kameoka S, Lentz S, et al. Activation of REST/NRSF target genes in neural stem cells is sufficient to cause neuronal differentiation. Mol Cell Biol 2004, 24(18):8018-8025
[62]Guardavaccaro D, Frescas D, Dorrello NV, et al. Control of chromosome stability by the beta-TrCP-REST-Mad2 axis. Nature 2008,452(7185):365-369
[63]Westbrook TF, Martin ES, Schlabach MR, et al. A genetic screen for candidate tumor suppressors identifies REST. Cell 2005,121(6):837-848.
[64]Coulson JM. Transcriptional regulation:cancer, neurons and the REST. Curr Biol 2005,15(17):R665-668
[65]Ariano P, Zamburlin P, D'Alessandro R, et al. Differential repression by the transcription factor REST/NRSF of the various Ca(2+) signalling mechanisms in pheochromocytoma PC12 cells. Cell Calcium.2010,47 (4):360-368
[66]Blom T, Tynninen 0, Puputti M, et al. Molecular genetic analysis of the REST/NRSF gene in nervous system tumors. Acta Neuropathol 2006, 112(4):483-490
[67]Shai A, Pitot HC, Lambert PF. p53 Loss synergizes with estrogen and papillomaviral oncogenes to induce cervical and breast cancers. Cancer Res 2008, 68(8):2622-2631
[68]Chen Y, Olopade OI. MYC in breast tumor progression. Expert Rev Anticancer Ther 2008,8(10):1689-1698
[69]Hagen AI, Bofin AM, Ytterhus B, et al. Amplification of TOP2A and HER-2 genes in breast cancers occurring in patients harbouring BRCA1 germline mutations. Acta Oncol 2007,46(2):199-203
[70]Ozer E, Sis B, Ozen E, et al. BRCA1, C-erbB-2, and H-ras gene expressions in young women with breast cancer. An immunohistochemical study. Appl Immunohistochem Mol Morphol 2000,8(1):12-18
[71]Nagai H, Harada H, Emi M. [Oncogene and tumor suppressor gene]. Nippon Rinsho 2000,58 Suppl:25-29
[72]Qureshi IA, Mehler MF. Regulation of non-coding RNA networks in the nervous system-what's the REST of the story? Neurosci Lett 2009,466(2):73-80
[73]Donahue LM, Reinhart AJ. POU domain genes are differentially expressed in the early stages after lineage commitment of the PNS-derived stem cell line, RT4-AC. Brain Res Dev Brain Res 1998,106(1-2):1-12
[74]Das C, Gadad SS, Kundu TK. Human positive coactivator 4 controls heterochromatinization and silencing of neural gene expression by interacting with REST/NRSF and CoREST. J Mol Biol,397(1):1-12
[75]Lee JH, Chai YG, Hersh LB. Expression patterns of mouse repressor element-1 silencing transcription factor 4 (REST4) and its possible function in neuroblastoma. J Mol Neurosci 2000,15(3):205-214
[76]Lee JH, Shimojo M, Chai YG, et al. Studies on the interaction of REST4 with the cholinergic repressor element-1/neuron restrictive silencer element. Brain Res Mol Brain Res 2000,80(1):88-98
[77]Shimojo M, Hersh LB. REST/NRSF-interacting LIM domain protein, a putative nuclear translocation receptor. Mol Cell Biol 2003,23(24):9025-9031
[78]Shimojo M. Characterization of the nuclear targeting signal of REST/NRSF. Neurosci Lett 2006,398(3):161-166
[79]Tabuchi A, Yamada T, Sasagawa S, et al. REST4-mediated modulation of REST/NRSF-silencing function during BDNF gene promoter activation. Biochem Biophys Res Commun 2002,290(1):415-420
[80]Kuwabara T, Hsieh J, Nakashima K, et al. A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 2004,116(6):779-793
[81]Westbrook TF, Hu G, Ang XL, et al. SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation. Nature 2008, 452(7185):370-374
[82]Tang W, Li Y, Yu D, et al. Targeting beta-transducin repeat-containing protein E3 ubiquitin ligase augments the effects of antitumor drugs on breast cancer cells. Cancer Res 2005,65(5):1904-1908
[83]Li Y, Clevenger CV, Minkovsky N, et al. Stabilization of prolactin receptor in breast cancer cells. Oncogene 2006,25(13):1896-1902
[84]Plotnikov A, Li Y, Tran TH, et al. Oncogene-mediated inhibition of glycogen synthase kinase 3 beta impairs degradation of prolactin receptor. Cancer Res 2008, 68(5):1354-1361
[85]Zhou BP, Deng J, Xia W, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 2004, 6(10):931-940
[86]Christensen WN, Strong EW, Bains MS, et al. Neuroendocrine differentiation in the glandular peripheral nerve sheath tumor. Pathologic distinction from the biphasic synovial sarcoma with glands. Am JSurg Pathol 1988,12(6):417-426
[87]Ishida E, Nakamura M, Shimada K, et al. Immunohistochemical analysis of neuroendocrine differentiation in prostate cancer. Pathobiology 2009,76(1):30-38
[88]Jones FS, Meech R. Knockout of REST/NRSF shows that the protein is a potent repressor of neuronally expressed genes in non-neural tissues. Bioessays 1999, 21(5):372-376
[89]Graeser M, Bosse K, Brosig M, et al. Association of hormone receptor status with grading, age of onset, and tumor size in BRCA1-associated breast cancer. Virchows Arch 2009,454(5):519-524
[90]Carnevale RP, Proietti CJ, Salatino M, et al. Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways. Mol Endocrinol 2007,21(6):1335-1358
[91]Anderson E. The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res 2002,4(5):197-201
[92]Murphy LC, Watson P. Steroid receptors in human breast tumorigenesis and breast cancer progression. Biomed Pharmacother 2002,56(2):65-77
[93]Ernberg IT. Oncogenes and tumor growth factors in breast cancer. A minireview. Acta Oncol 1990,29(3):331-334
[94]Brown RE. HER-2/neu-Positive breast carcinoma:molecular concomitants by proteomic analysis and their therapeutic implications. Ann Clin Lab Sci 2002, 32(1):12-21
[95]Cao W, Zhang B, Liu Y, et al. High-level SLP-2 expression and HER-2/neu protein expression are associated with decreased breast cancer patient survival. Am J Clin Pathol 2007,128(3):430-436
[96]Sekine I, Shimizu C, Nishio K, et al. A literature review of molecular markers predictive of clinical response to cytotoxic chemotherapy in patients with breast cancer. Int J Clin Oncol 2009,14(2):112-119
[97]Azizun N, Bhurgri Y, Raza F,et al. Comparison of ER, PR and HER-2/neu (C-erb B 2) reactivity pattern with histologic grade, tumor size and lymph node status in breast cancer. Asian Pac J Cancer Prev 2008,9(4):553-556
[98]Hussein MR, Abd-Elwahed SR, Abdulwahed AR. Alterations of estrogen receptors, progesterone receptors and c-erbB2 oncogene protein expression in ductal carcinomas of the breast. Cell Biol Int 2008,32(6):698-707
[99]Faratian D, Kay C, Robson T, et al. Automated image analysis for high-throughput quantitative detection of ER and PR expression levels in large-scale clinical studies: the TEAM Trial Experience. Histopathology 2009,55(5):587-593
[100]Parise CA, Bauer KR, Brown MM, et al. Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California,1999-2004. Breast J 2009,15(6):593-602
[101]Elsberger B, Tan BA, Mitchell TJ, et al. Is expression or activation of Src kinase associated with cancer-specific survival in ER-, PR-and HER2-negative breast cancer patients? Am J Pathol 2009,175(4):1389-1397
[102]Fernandes RC, Bevilacqua JL, Soares IC, et al. Coordinated expression of ER, PR and HER2 define different prognostic subtypes among poorly differentiated breast carcinomas. Histopathology 2009,55(3):346-352
[103]Wu J, Xie X. Comparative sequence analysis reveals an intricate network among REST, CREB and miRNA in mediating neuronal gene expression. Genome Biol 2006,7(9):R85
[104]Zuccato C, Belyaev N, Conforti P, et al. Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington's disease. JNeurosci 2007,27(26):6972-6983
[105]Barrachina M, Moreno J, Juves S, et al. Target genes of neuron-restrictive silencer factor are abnormally up-regulated in human myotilinopathy. Am J Pathol 2007, 171(4):1312-1323
[106]Armisen R, Fuentes R, Olguin P, et al. Repressor element-1 silencing transcription/neuron-restrictive silencer factor is required for neural sodium channel expression during development of Xenopus. JNeurosci 2002,22(19):8347-8351
[107]Eggen BJ, Mandel G. Regulation of sodium channel gene expression by transcriptional silencing. Dev Neurosci 1997,19(1):25-26
[108]Garcia-Sanchez R, Ayala-Lujan J, Hernandez-Perez A, et al. Identification of repressor element 1 in cytochrome P450 genes and their negative regulation by RE1 silencing transcription factor/neuron-restrictive silencer factor. Biochim Biophys Acta 2003,1620(1-3):39-46
[109]Kallunki P, Edelman GM, Jones FS. Tissue-specific expression of the L1 cell adhesion molecule is modulated by the neural restrictive silencer element. J Cell Biol 1997,138(6):1343-1354
[110]Otto SJ, McCorkle SR, Hover J, et al. A new binding motif for the transcriptional repressor REST uncovers large gene networks devoted to neuronal functions. J Neurosci 2007,27(25):6729-6739
[111]Schoenherr CJ, Paquette AJ, Anderson DJ. Identification of potential target genes for the neuron-restrictive silencer factor. Proc Natl Acad Sci U S A 1996, 93(18):9881-9886
[112]Gillies S, Haddley K, Vasiliou S, et al. The human neurokinin B gene, TAC3, and its promoter are regulated by Neuron Restrictive Silencing Factor (NRSF) transcription factor family. Neuropeptides 2009,43(4):333-340
[113]Greco SJ, Smirnov SV, Murthy RG, et al. Synergy between the RE-1 silencer of transcription and NFkappaB in the repression of the neurotransmitter gene TAC1 in human mesenchymal stem cells. J Biol Chem 2007,282(41):30039-30050
[114]Lonnerberg P, Schoenherr CJ, Anderson DJ, et al. Cell type-specific regulation of choline acetyltransferase gene expression. Role of the neuron-restrictive silencer element and cholinergic-specific enhancer sequences. J Biol Chem 1996, 271(52):33358-33365
[115]Weissman AM. How much REST is enough? Cancer Cell 2008,13(5):381-383.
[116]Moss AC, Jacobson GM, Walker LE, et al. SCG3 transcript in peripheral blood is a prognostic biomarker for REST-deficient small cell lung cancer. Clin Cancer Res 2009,15(1):274-283
[117]Reddy BY, Greco SJ, Patel PS, et al. RE-1-silencing transcription factor shows tumor-suppressor functions and negatively regulates the oncogenic TAC1 in breast cancer cells. Proc Natl Acad Sci U S A 2009,106(11):4408-4413
[118]Hannon GJ, Conklin DS. RNA interference by short hairpin RNAs expressed in vertebrate cells. Methods Mol Biol 2004,257:255-266
[119]Aravin AA, Vagin VV, Naumova NM, et al. [The phenomenon of RNA interference and development of organism]. Ontogenez 2002,33(5):349-360
[120]Harborth J, Elbashir SM, Bechert K, et al. Identification of essential genes in cultured mammalian cells using small interfering RNAs. J Cell Sci 2001,114(Pt 24):4557-4565
[121]Kumar R, Adams B, Oldenburg A, et al. Characterisation and expression of a PP1 serine/threonine protein phosphatase (PfPP1) from the malaria parasite, Plasmodium falciparum:demonstration of its essential role using RNA interference. Malar J 2002,1-5
[122]Mukherjea D, Jajoo S, Whitworth C, et al. Short interfering RNA against transient receptor potential vanilloid 1 attenuates cisplatin-induced hearing loss in the rat. J Neurosci 2008,28(49):13056-13065
[123]Montgomery MK, Xu S, Fire A. RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans. Proc Natl Acad Sci U S A 1998, 95(26):15502-15507
[124]Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998,391(6669):806-811
[125]Elbashir SM, Lendeckel W, Tuschl T. RNA interference is mediated by 21-and 22-nucleotide RNAs. Genes Dev 2001,15(2):188-200
[126]Bric A, Miething C, Bialucha CU, et al. Functional identification of tumor-suppressor genes through an in vivo RNA interference screen in a mouse lymphoma model. Cancer Cell 2009,16(4):324-335
[127]Cerutti H. RNA interference:traveling in the cell and gaining functions? Trends Genet 2003,19(1):39-46
[128]Hamada M, Ohtsuka T, Kawaida R, et al. Effects on RNA interference in gene expression (RNAi) in cultured mammalian cells of mismatches and the introduction of chemical modifications at the 3'-ends of siRNAs. Antisense Nucleic Acid Drug Dev 2002,12(5):301-309
[129]Golding MC, Long CR, Carmell MA, et al. Suppression of prion protein in livestock by RNA interference. Proc Natl Acad Sci U S A 2006,103(14):5285-5290
[130]Gupta S, Schoer RA, Egan JE, et al. Inducible, reversible, and stable RNA interference in mammalian cells. Proc Natl Acad Sci USA 2004,101(7):1927-1932
[131]Borkhardt A. Blocking oncogenes in malignant cells by RNA interference-new hope for a highly specific cancer treatment? Cancer Cell 2002,2(3):167-168
[132]Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002,2(3):243-247
[133]Martinez MA, Clotet B, Este JA. RNA interference of HIV replication. Trends Immunol 2002,23(12):559-561
[134]Martinez MA, Gutierrez A, Armand-Ugon M, et al. Suppression of chemokine receptor expression by RNA interference allows for inhibition of HIV-1 replication. AIDS 2002,16(18):2385-2390
[135]Saksela K. [RNA interference in the prevention of viral diseases?]. Duodecim 2002, 118(21):2191-2198
[136]Silva JM, Hammond SM, Hannon GJ. RNA interference:a promising approach to antiviral therapy? Trends Mol Med 2002,8(11):505-508
[137]Haiman CA, Stram DO, Cheng I, et al. Common genetic variation at PTEN and risk of sporadic breast and prostate cancer. Cancer Epidemiol Biomarkers Prev 2006, 15(5):1021-1025
[138]McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 2006,46:249-279
[139]Weng LP, Brown JL, Baker KM, et al. PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Hum Mol Genet 2002,11(15):1687-1696
[140]Yu Y, Feig LA. Involvement of R-Ras and Ral GTPases in estrogen-independent proliferation of breast cancer cells. Oncogene 2002,21(49):7557-7568
[141]Shin I, Kim S, Song H, et al. H-Ras-specific activation of Rac-MKK3/6-p38
pathway:its critical role in invasion and migration of breast epithelial cells. J Biol Chem 2005,280(15):14675-14683
[142]Jones RA, Campbell CI, Gunther EJ, et al. Transgenic overexpression of IGF-IR disrupts mammary ductal morphogenesis and induces tumor formation. Oncogene 2007,26(11):1636-1644
[143]Lee AV, Taylor ST, Greenall J, et al. Rapid induction of IGF-IR signaling in normal and tumor tissue following intravenous injection of IGF-I in mice. Horm Metab Res 2003,35(11-12):651-655
[144]Schaefer JS, Zhang M. Role of maspin in tumor metastasis and angiogenesis. Curr Mol Med 2003,3(7):653-658
[145]Streuli CH. Maspin is a tumour suppressor that inhibits breast cancer tumour metastasis in vivo. Breast Cancer Res 2002,4(4):137-140
[146]Xiong LJ, Liang CH, Deng HY. [Relevant factors of nm23 protein expression and dangerous factors of bone metastasis in breast cancer]. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2004,29(1):75-78
[147]Wu M, Wu ZF, Kumar-Sinha C, et al. RhoC induces differential expression of genes involved in invasion and metastasis in MCF10A breast cells. Breast Cancer Res Treat 2004,84(1):3-12
[148]Huber MA, Azoitei N, Baumann B, et al. NF-kappaB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 2004,114(4):569-581
[149]Shiomi T, Okada Y. MT1-MMP and MMP-7 in invasion and metastasis of human cancers. Cancer Metastasis Rev 2003,22(2-3):145-152
[150]Wang FM, Liu HQ, Liu SR, et al. SHP-2 promoting migration and metastasis of MCF-7 with loss of E-cadherin, dephosphorylation of FAK and secretion of MMP-9 induced by IL-lbeta in vivo and in vitro. Breast Cancer Res Treat 2005,89(1):5-14
[151]Wang X, Nagase H, Watanabe T, et al. Inhibition of MMP-9 transcription and suppression of tumor metastasis by pyrrole-imidazole polyamide. Cancer Sci 2010, 101(3):759-66
[152]Hao L, Zhang C, Qiu Y, et al. Recombination of CXCR4, VEGF, and MMP-9 predicting lymph node metastasis in human breast cancer. Cancer Lett 2007, 253(1):34-42
[153]Suarez-Cuervo C, Merrell MA, Watson L, et al. Breast cancer cells with inhibition of p38alpha have decreased MMP-9 activity and exhibit decreased bone metastasis in mice. Clin Exp Metastasis 2004,21(6):525-533
[154]Liu Z, Liu M, Niu G, et al. Genome-wide identification of target genes repressed by the zinc finger transcription factor REST/NRSF in the HEK 293 cell line. Acta Biochim Biophys Sin (Shanghai) 2009,41(12):1008-1017 的研究结果发现肿瘤分级越高,生存率越低;分级低者NE细胞更常见,但NE细胞阳性和阴性的肿瘤,5年生存率均无差异,认为NED程度对前列腺癌的预后无实际价值。同样,卵巢上皮性肿瘤的研究中发现,神经内分泌分化的出现可能与患者不良预后有关[33]。然而,在乳腺癌伴神经内分泌分化的研究中,有学者称伴神经内分泌分化的乳腺癌预后较好,也有研究显示其与预后无相关性。故神经内分泌分化的出现与预后的关系值得进一步的探索与研究。5、结语
通过上述的分析与研究,我们不难看出,恶性肿瘤细胞出现神经内分泌分化现象对于肿瘤本身的发生与发展,及对肿瘤的预后均有着较为重要的影响。而且,研究表明,在不同的肿瘤中,神经内分泌分化的出现会产生截然不同的效果。如在前列腺癌的研究中,大部分的研究显示伴神经内分泌分化的肿瘤治疗效果差,预后不好；卵巢上皮性肿瘤中出现的NE细胞可以使其周围细胞的抗凋亡能力增强,有利于肿瘤的侵袭与转移；而伴神经内分泌分化的非小细胞肺癌对化疗的敏感性增强；乳腺癌中有报道称,伴神经内分泌分化与肿瘤预后无关甚至有较好的预后。这些看似矛盾的现象需要医学工作者辨证地对待,深入研究神经内分泌分化这一现象出现的原因与意义。
[1]Tavassoli Fa, Devilee P. World Health Orgnization classification of tumors pathology & genetics, tumors of the breast and female genital organs. Lyon:IACR Press,2003,32-36
[2]Shaoul R, Hong D, Okada Y, Cutz E, Marcon MA. Lineage development in a patient without goblet, paneth, and enteroendocrine cells:a clue for intestinal epithelial differentiation. Pediatr Res.2005;58(3):492-498
[3]Kim J, Adam RM, Freeman MR. Activation of the Erk mitogen-activated protein kinase pathway stimulates neuroendocrine differentiation in LNCaP cells independently of cell cycle withdrawal and STAT3 phosphorylation. Cancer Res.2002,62(5):1549-1554
[4]Horiatis D, Wang Q, Pinski J. A new screening system for proliferation-independent anti-cancer agents. Cancer Lett.2004,210(1):119-124
[5]Pinski J, Wang Q, Quek ML, et al. Genistein-induced neuroendocrine differentiation of prostate cancer cells. Prostate.2006,66(11): 1136-1143
[6]Schalken JA, van Leenders G. Cellular and molecular biology of the prostate:stem cell biology. Urology.2003;62(5 Suppl 1):11-20
[7]Bajetta E, Ferrari L, Martinetti A, et al. Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer,1999,86 (5): 858-865
[8]Jongsma J, Oomen MH, Noordzij MA, et al. Androgen deprivation of the PC-310 [correction of prohormone convertase-310] human prostate cancer model system induces neuroendocrine differentiation. Cancer Res. 2000;60(3):741-748
[9]Jiborn T, Abrahamson M, Gadaleanu V, et al. Aberrant expression of cystatin C in prostate cancer is associated with neuroendocrine differentiation. BJU Int.2006;98(1):189-196
[10]Figueiredo KA, Palmer JB, Cox ME, et al. Demonstration of upregulated H2 relaxin mRNA expression during neuroendocrine differentiation of LNCaP prostate cancer cells and production of biologically active mammalian recombinant 6 histidine-tagged H2 relaxin. Ann N Y Acad Sci. 2005:1041:320-327
[11]Iyoda A, Hiroshima K, Toyozaki T et al. Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology. Cancer 2001; 91(11):1992-2000
[12]Kimura H, Yamaguchi T, Nishino K, et al. Clinical significance of serum neuronspecific enlase on non-small cell lung cancer. Nihon Kokyuk Gakkai Zasshi,1998:36128-32
[13]Satoh H, Ishikawa H, Kurishima K, et al. Cut-off levels of NSE to differentiate SCLC from NSCLC. J Oncol Rep,2002; 9(3):581-3
[14]欧阳能太,陈国勤,钟南山等.非小细胞肺癌神经内分泌表达的检测及临床意义。中华结核和呼吸杂志.2001,24：90-92
[15]Di Sant'Agnese PA. Neuroendocrine differentiation in carcinoma of the prostate. Diagnostic, prognostic, and therapeutic implications. Cancer, 1992,70:254-268
[16]DiSant'Agnese PA. Neuroendocrine differentiation in carcinoma of the prostate:diagnostic, prognostic, and therapeutic implications. Cancer. 1993,70:254-268
[17]Vashchenko N, Abrahamsson PA. Neuroendocrine differentiation in prostate cancer:implications for new treatment modalities. Eur Urol.2005, 47(2):147-155
[18]Nakada SY, diSant'Agnese PA, Moynes RA et al. The androgen receptor status of neuroendocrine cells in human benign and malignant prostatic tissue. Cancer Research.1933,53:1967-1970
[19].Hansson J, Abrahamsson PA. Neuroendocrine differentiation in prostatic carcinoma. Scand J Urol Nephrol Suppl.2003, (212):28-36
[20]Lepidi H, Monges G, Delpero JR, et al. Gastric adenocarcinoma with an endocrine component. Report of nine cases. Ann Pathol,1993,13 (1): 17-22
[21]Waldum HL, Aase S, Kvetnoi I, et al. Neuroendocrine differentiation in human gastric carcinoma. Cancer,1998,83 (3):435-443
[22]Luisa GM, Achille P. Carciond tumors:review of a single institution experience. Ann oncol,2000,11(2):58-63
[23]Lapertosa G. Histogenetic considerations on mucinous cystomas of the ovary based on histochemical and immunohistochemical findings. Pathologica,1989,81(1074):381-401
[24]Lin M, Hanai J, Wada A, et al. Argyrophilia in ovarian serous tumors. A comparative study in 127 epithelial ovarian tumors. Histol Histopathol,1991,6(4):477-484
[25]Turitto G, Frattolillo A, Iodice P, et al. Neuroendocrine features of prostatic tumors:state of the art. Recenti Prog Med,2003,94(12): 568-572
[26]Furlan D, Cerutti R, Uccella S, et al. Different molecular p rofiles characterize well2differentiated endocrine tumors and poorly differentiated endocrine carcinomas of the gastroentero pancreatic tract. Clin Cancer Res,2004,10 (3):947-957
[27]Segal N, Cohen R, Haffejee Z, et al. BCL-2 proto-onocogene expression in prostate cancer and its relationship to the prostate neuroendocrine cell. Arch Pathol Lab Med,1994,118:616-618
[28]Ruff in IE, Bongiovann IM, Cavallo A, et al. The significance of associated p re-invasive lesions in patients resected for primary lung neop lasms. Eur J Cardiothorac Surg,2004,26(1):165-172
[29]Adwer KL; Ppel G. Neuroendokrine Tumoren des Gastrointestinaltrakts. Pathologe,2003,24 (4):287-296
[30]Tanaka M, Suzuki Y. Progression of p rostate cancer to neuroendocrine cell tumor. Inter J Urol,2001,8 (8):431-436
[31]Cohen R, Glezereson G, Haffejee Z. Neuroendocrine cells:a new prognostic parameter in prostate cancer. Br J Urol,1991,58:258-262
[32]Allen FJ, Van Velden DJ, Heyns CF. Are neuroendocrine cells of practical value as an independent prognostic parameter in prostate cancer. Br J Urol,1995,75(6):751-754
[33]蒋立艳,王自能,路妍妍,等。卵巢上皮性肿瘤神经内分泌分化及其意义。广东医学2007；28(2)：248-251