上皮性卵巢癌参与免疫逃逸相关基因Igs，FOXP3的表达研究
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摘要
上皮性卵巢癌患者体内多存在机体免疫功能的异常,主要表现为肿瘤局部的细胞免疫普遍受抑制,其效应细胞,如CD4+T细胞、CD8+T细胞、NK细胞功能减低,而在体液免疫方面却呈现出难以理解的患者外周血Ig水平升高。为揭示上皮性卵巢癌免疫反应低下的诱导和维持的相关机制,本论文进行了以下两部分的实验研究:
第一部分:应用免疫组织化学染色法研究IgG、IgA、IgM、IgD、IgE在上皮性卵巢癌组织芯片(含上皮性卵巢癌177例)和50例卵巢上皮性良性肿瘤上皮组织中的表达特点,分析IgG、IgA、IgM、IgD、IgE的表达强度与上皮性卵巢癌病理分级的相关性。结果发现Ig在卵巢上皮性癌组织中高表达,并存在大量Ig细胞外分泌的形式;IgG、IgA、IgM、IgD、IgE在上皮性卵巢癌组织的表达水平明显高于卵巢良性肿瘤上皮组织(P<0.001);IgG、IgA、IgM、IgD、IgE的表达强度与肿瘤病理分级成正相关(P<0.001),肿瘤的分化程度越低, Ig的表达强度越强。本研究的创新点在于在国内外首次进行Igs在组织学领域中大样本的观察研究。
第二部分:1.应用免疫组织化学染色法应检测FOXP3在46例上皮性卵巢癌组织中的表达。2.应用逆转录聚合酶链反应(RT-PCR)检测SKOV3和CAOV3细胞中FOXP3 mRNA的表达,测序,进行序列及开放阅读框(ORF)的比对;应用免疫细胞化学染色法检测FOXP3蛋白在SKOV3和CAOV3细胞中的表达。3.进行FOXP3特异的siRNA干涉实验,观察siRNA干涉后SKOV3细胞FOXP3 mRNA的表达变化,通过流式细胞术检测siRNA干涉后48、72、96、120小时FOXP3蛋白的表达,并与Non-silencing siRNA组进行比较。结果:1.在36/46(78.3%)例卵巢上皮性癌组织中检测到癌细胞表达FOXP3蛋白;2.在SKOV3和CAOV3细胞中均检测到FOXP3 mRNA的表达;SKOV3细胞的FOXP3 mRNA片段与GeneBank中的人FOXP3 mRNA中的序列一致,而CAOV3细胞的FOXP3 mRNA片段有1个突变位点,造成1个亮氨酸转变为1个苯丙氨酸;FOXP3蛋白在SKOV3细胞中定位于细胞核,而在CAOV3细胞中定位于细胞浆。3.发现siRNA干涉后48h可有效抑制FOXP3 mRNA的表达,并且干涉后48、72、96、120小时siRNA组FOXP3蛋白表达低于Non-silencing siRNA组比较。本研究的创新点在于在国内外首次证明上皮性卵巢癌和上皮性卵巢癌细胞系可表达转录因子FOXP3,为上皮性卵巢癌细胞逃逸局部免疫效应细胞的攻击而不断增殖、浸润和转移的机制提供了重要的理论依据。
Ovarian tumors is a common female genital malignancy, one of the three. 5-year survival rate around 30%, has become a threat to women's lives and health of the main tumor. Among them, the source of the tumor epithelial primary ovarian tumors account for 50% -70%. Therefore, the epithelial ovarian cancer research of great significance. The current general view is that cell-mediated immunity in the anti-tumor immunity play a leading role, including CD8+, CD4+ T cells, NK cells, macrophages and DC of the anti-tumor effects. And humoral immunity can also be caused by apoptosis or growth inhibition of the signal generated, complemen-t-mediated target cell lysis (CDC) and ADCC to support the role of T cells in anti-tumor effects. Epithelial ovarian cancer patients more than the existence of abnormal immune function, mainly for cancer patients by inhibiting cell-mediated immunity in general, the effector cells, such as CD4+ T cells, CD8+ T cells, NK cell function to reduce, and in the humoral immune show aspects of the peripheral blood of patients with difficult to understand Ig levels. For epithelial ovarian cancer reveals the immune response of the induction and maintenance of the lower of the relevant mechanisms, the paper conducted the following experimental study of two parts:
1 IgG, IgA, IgM, IgD, IgE expressions in the tissues of epithelial ovarian carcinoma
Long time ago clinical tumors have found that some patients with the IgG, IgA, IgM and plasma of circulating immune complexes (CIC) levels were significantly higher, even of monoclonal immunoglobulin of hyperlipidemia, these antibodies can be normal cells or tumor cell-specific binding, it is known as tumor-reactive antibodies, these antibodies often precedes the increase in poor prognosis. 20th century 80's, it was found that the existence of a tumor in patients with immune suppression factor can inhibit the function of host cells, this inhibitory effect was found in the Ig and blood, and it has a prevalence of blood through the removal of Ig molecules to treat cancer method, experimental results showed that after removal of Ig tumor necrosis can be significant.
In 2001 Professor Zhang Youhui study group had ascites from ovarian cancer patients with isolated an immune inhibitory factor, it can effectively inhibit the proliferation of peripheral blood T lymphocytes, and unexpectedly found that the factor of SDS-PAGE electrophoresis patterns with IgG completely consistent. Further through the flow cytometry found that ascites IgG positive cancer cells was stronger than that of the lymphocytes. The traditional theory of immunology, Ig gene only in the course of B cell development before rearrangement occurs, but in recent years, research has suggested that malignant epithelial cells can occur in Ig gene rearrangement and generation of Ig molecules.
The experimental application of immunohistochemistry in epithelial ovarian cancer tissue microarray (epithelial ovarian cancer with 177 cases) and 50 cases of benign ovarian epithelial tissue in IgG, IgA, IgM, IgD, IgE specific staining, and the following research: (1) observation of IgG, IgA, IgM, IgD, IgE in patients with epithelial ovarian carcinoma characteristics. Igs was found in epithelial ovarian cancer in high-expression will be positive staining mainly in cytoplasm of cancer cells, and the existence of a large number of Igs secreted extracellular form; (2) of the Ig staining intensity score, compared IgG, IgA, IgM, IgD, IgE in epithelial ovarian cancer and benign ovarian epithelial tissue differences, results showed that IgA, IgM, IgD, IgE in epithelial ovarian cancer tissues was significantly higher than benign ovarian epithelium (P< 0.001); (3) Analysis of IgG, IgA, IgM, IgD, IgE staining intensity and tumor histological grade of relevance, results showed that IgG, IgA, IgM, IgD, IgE expression intensity and histological grade of tumor was positively correlated (P < 0.001), tumor of the lower degree of differentiation, Ig stronger expression.
This experiment the following conclusions: (1) Epithelial ovarian cancer cells express high IgG, IgA, IgM, IgD, IgE, and IgG, IgA, IgM, IgD, IgE expression in the existence of a large number of exocrine cells of the phenomenon. Epithelial ovarian cancer cells to secrete Igs to the cancer tissue is epithelial ovarian cancer to participate in an important mechanism for immune escape. (2) Epithelial ovarian cancer, the lower the degree of malignancy, IgG, IgA, IgM, IgD, IgE were in weaker expressions; the higher the degree of malignancy, IgG, IgA, IgM, IgD, IgE were in stronger expressions. Abnormal expressions of IgG, IgA ,IgM, IgD, IgE in ovarian epithelial carcinoma indicate what were relation of occurring and development of ovarian epithelial carcinoma
In this experiment IgG, IgA, IgM, IgD, IgE were studied in the field of histological observation of large sample studies for the first time. The results of this study will provide a theoretical basis Igs are involved in mechanism of epithelial ovarian cancer cell immune escape mechanisms and clues to the biological treatment of Igs for the targets in epithelial ovarian cancer cells
2 FOXP3 expression in epithelial ovarian cancer cells
CD4+CD25+ regulatory T cells (Treg) is the body to“active”approach to maintaining stability in autoimmune channels can inhibit inappropriate immune response, immune response can limit the scope, extent and time , while maintaining its own stability and the prevention of autoimmune diseases and transplant rejection control play very important role in the protection. CD4+CD25+ Treg cells suppress the immune system in different types of cell differentiation and effector functions: conventional CD4+ and CD8+ T lymphocytes , NKT cells, B cells, dendritic cells and monocytes / macrophages. However, recent studies have found in the tumor micro-environment in the CD4+CD25+ Treg cells increased significantly, and inhibit tumor immune effect. Fork-like transcription factor FOXP3 is the first immunosuppressive cells, CD4+CD25+ Treg development in the thymus, peripheral maintenance of the expression and function of an important regulator of genes that will enable primary CD4+CD25- T cells into CD4+CD25+ Treg. In 2001, Bnmkow foxp3 genes was reported for the first time studying the of sf mice. Sf mice is due to foxp3 gene DNA-binding domain containing the two base frameshift insertion, caused by client protein C deficiency and the forkhead domain of transcription can not be regulation. sf mice CD4+ T cell-mediated immunity imbalance, fatal disease of lymphocyte proliferation and with multiple organ infiltration, lymphocyte infiltration and organ non-specific IL-2, IL-4, IL-10, IFN-γ, etc. a large number of secreted cytokines. Homologous human FOXP3 gene mutations can cause human diseases of immune disorders, endocrine diseases, enteropathy, X chromosome-linked syndrome (IPEX), performance for the full immune disorders, associated with autoimmune endocrine diseases such as early onsetⅠtype diabetes and thyroiditis, in some cases accompanied by severe atopic atopy, including eczema, food allergy and eosinophilic inflammation.
Usually found that the immune effects of tumor cells such as CD4+ T cells, CD8+ T cells, NK cell proliferation and activity were of the lower inhibitory ability. Lower of immune response exists in the tumor micro-environment.In order to explore the local epithelial ovarian cancer-related immune mechanisms Participation, this study conducted the following experiment:
(1)Study of FOXP3 in ovarian epithelial carcinoma tissues Application of immunohistochemical staining method we detected FOXP3 expreession in 46 cases of epithelial ovarian cancer. 36 cases of epithelial ovarian cancer was detected in FOXP3 expression, FOXP3 staining was brown showed the positioning of the nucleus in cancer cells.
(2)Study of FOXP3 expression in epithelial ovarian carcinoma cell lines Detecting FOXP3 expression in CAOV3 in SKOV3 cells. Application of reverse transcription polymerase chain reaction (RT-PCR) we detected the expression of two cells’FOXP3 mRNA expressions, sequencing, sequence and open reading frame (ORF) of the ratio; Application of immunocytochemical staining FOXP3 protein in SKOV3 cells and CAOV3 cells.
The results of the two cells were detected in the expression of FOXP3 mRNA. In SKOV3 cells FOXP3 mRNA fragments were in the same sequence of the GeneBank FOXP3 mRNA; CAOV3 cells FOXP3 mRNA fragments have a mutation, resulting in a leucine into a phenylalanine; FOXP3 protein in SKOV3 cells located in the nucleus, and in CAOV3 cells located in cytoplasm.
(3)FOXP3-specific siRNA interference experiment Observation of the expression of FOXP3 mRNA expression and FOXP3 protein expression by flow cytometry in SKOV3 cells after siRNA interference 48,72,96,120 hours after siRNA interference,comparing with Non-silencing siRNA group.
The results showed that 48h after siRNA interference can effectively inhibit the expression of FOXP3 mRNA and inhibit the FOXP3 protein expression after interfere 48,72,96,120 hours in siRNA group than Non-silencing siRNA group. In this study, the following conclusions:
(1) Epithelial ovarian cancer cells to express FOXP3, may be of an important mechanism epithelial ovarian cancer cells escape immune effector cells’attack constantly proliferation, invasion and metastasis.
(2) Epithelial ovarian cancer cells can express FOXP3, may be one of important mechanism the increasing CD4+ CD25+ Treg cells in the location of epithelial ovarian cancer tissue.
In this study, we first the time demonstrate epithelial ovarian cancer and ovarian cancer cell lines can express transcription factor FOXP3, will provide important theoretical basis for reveal the tumor low immune inhibition mechanisms in the locations of epithelial ovarian cancer tissue and important clues for epithelial ovarian cancer immune therapy provide.
第一部分:应用免疫组织化学染色法研究IgG、IgA、IgM、IgD、IgE在上皮性卵巢癌组织芯片(含上皮性卵巢癌177例)和50例卵巢上皮性良性肿瘤上皮组织中的表达特点,分析IgG、IgA、IgM、IgD、IgE的表达强度与上皮性卵巢癌病理分级的相关性。结果发现Ig在卵巢上皮性癌组织中高表达,并存在大量Ig细胞外分泌的形式;IgG、IgA、IgM、IgD、IgE在上皮性卵巢癌组织的表达水平明显高于卵巢良性肿瘤上皮组织(P<0.001);IgG、IgA、IgM、IgD、IgE的表达强度与肿瘤病理分级成正相关(P<0.001),肿瘤的分化程度越低, Ig的表达强度越强。本研究的创新点在于在国内外首次进行Igs在组织学领域中大样本的观察研究。
第二部分:1.应用免疫组织化学染色法应检测FOXP3在46例上皮性卵巢癌组织中的表达。2.应用逆转录聚合酶链反应(RT-PCR)检测SKOV3和CAOV3细胞中FOXP3 mRNA的表达,测序,进行序列及开放阅读框(ORF)的比对;应用免疫细胞化学染色法检测FOXP3蛋白在SKOV3和CAOV3细胞中的表达。3.进行FOXP3特异的siRNA干涉实验,观察siRNA干涉后SKOV3细胞FOXP3 mRNA的表达变化,通过流式细胞术检测siRNA干涉后48、72、96、120小时FOXP3蛋白的表达,并与Non-silencing siRNA组进行比较。结果:1.在36/46(78.3%)例卵巢上皮性癌组织中检测到癌细胞表达FOXP3蛋白;2.在SKOV3和CAOV3细胞中均检测到FOXP3 mRNA的表达;SKOV3细胞的FOXP3 mRNA片段与GeneBank中的人FOXP3 mRNA中的序列一致,而CAOV3细胞的FOXP3 mRNA片段有1个突变位点,造成1个亮氨酸转变为1个苯丙氨酸;FOXP3蛋白在SKOV3细胞中定位于细胞核,而在CAOV3细胞中定位于细胞浆。3.发现siRNA干涉后48h可有效抑制FOXP3 mRNA的表达,并且干涉后48、72、96、120小时siRNA组FOXP3蛋白表达低于Non-silencing siRNA组比较。本研究的创新点在于在国内外首次证明上皮性卵巢癌和上皮性卵巢癌细胞系可表达转录因子FOXP3,为上皮性卵巢癌细胞逃逸局部免疫效应细胞的攻击而不断增殖、浸润和转移的机制提供了重要的理论依据。
Ovarian tumors is a common female genital malignancy, one of the three. 5-year survival rate around 30%, has become a threat to women's lives and health of the main tumor. Among them, the source of the tumor epithelial primary ovarian tumors account for 50% -70%. Therefore, the epithelial ovarian cancer research of great significance. The current general view is that cell-mediated immunity in the anti-tumor immunity play a leading role, including CD8+, CD4+ T cells, NK cells, macrophages and DC of the anti-tumor effects. And humoral immunity can also be caused by apoptosis or growth inhibition of the signal generated, complemen-t-mediated target cell lysis (CDC) and ADCC to support the role of T cells in anti-tumor effects. Epithelial ovarian cancer patients more than the existence of abnormal immune function, mainly for cancer patients by inhibiting cell-mediated immunity in general, the effector cells, such as CD4+ T cells, CD8+ T cells, NK cell function to reduce, and in the humoral immune show aspects of the peripheral blood of patients with difficult to understand Ig levels. For epithelial ovarian cancer reveals the immune response of the induction and maintenance of the lower of the relevant mechanisms, the paper conducted the following experimental study of two parts:
1 IgG, IgA, IgM, IgD, IgE expressions in the tissues of epithelial ovarian carcinoma
Long time ago clinical tumors have found that some patients with the IgG, IgA, IgM and plasma of circulating immune complexes (CIC) levels were significantly higher, even of monoclonal immunoglobulin of hyperlipidemia, these antibodies can be normal cells or tumor cell-specific binding, it is known as tumor-reactive antibodies, these antibodies often precedes the increase in poor prognosis. 20th century 80's, it was found that the existence of a tumor in patients with immune suppression factor can inhibit the function of host cells, this inhibitory effect was found in the Ig and blood, and it has a prevalence of blood through the removal of Ig molecules to treat cancer method, experimental results showed that after removal of Ig tumor necrosis can be significant.
In 2001 Professor Zhang Youhui study group had ascites from ovarian cancer patients with isolated an immune inhibitory factor, it can effectively inhibit the proliferation of peripheral blood T lymphocytes, and unexpectedly found that the factor of SDS-PAGE electrophoresis patterns with IgG completely consistent. Further through the flow cytometry found that ascites IgG positive cancer cells was stronger than that of the lymphocytes. The traditional theory of immunology, Ig gene only in the course of B cell development before rearrangement occurs, but in recent years, research has suggested that malignant epithelial cells can occur in Ig gene rearrangement and generation of Ig molecules.
The experimental application of immunohistochemistry in epithelial ovarian cancer tissue microarray (epithelial ovarian cancer with 177 cases) and 50 cases of benign ovarian epithelial tissue in IgG, IgA, IgM, IgD, IgE specific staining, and the following research: (1) observation of IgG, IgA, IgM, IgD, IgE in patients with epithelial ovarian carcinoma characteristics. Igs was found in epithelial ovarian cancer in high-expression will be positive staining mainly in cytoplasm of cancer cells, and the existence of a large number of Igs secreted extracellular form; (2) of the Ig staining intensity score, compared IgG, IgA, IgM, IgD, IgE in epithelial ovarian cancer and benign ovarian epithelial tissue differences, results showed that IgA, IgM, IgD, IgE in epithelial ovarian cancer tissues was significantly higher than benign ovarian epithelium (P< 0.001); (3) Analysis of IgG, IgA, IgM, IgD, IgE staining intensity and tumor histological grade of relevance, results showed that IgG, IgA, IgM, IgD, IgE expression intensity and histological grade of tumor was positively correlated (P < 0.001), tumor of the lower degree of differentiation, Ig stronger expression.
This experiment the following conclusions: (1) Epithelial ovarian cancer cells express high IgG, IgA, IgM, IgD, IgE, and IgG, IgA, IgM, IgD, IgE expression in the existence of a large number of exocrine cells of the phenomenon. Epithelial ovarian cancer cells to secrete Igs to the cancer tissue is epithelial ovarian cancer to participate in an important mechanism for immune escape. (2) Epithelial ovarian cancer, the lower the degree of malignancy, IgG, IgA, IgM, IgD, IgE were in weaker expressions; the higher the degree of malignancy, IgG, IgA, IgM, IgD, IgE were in stronger expressions. Abnormal expressions of IgG, IgA ,IgM, IgD, IgE in ovarian epithelial carcinoma indicate what were relation of occurring and development of ovarian epithelial carcinoma
In this experiment IgG, IgA, IgM, IgD, IgE were studied in the field of histological observation of large sample studies for the first time. The results of this study will provide a theoretical basis Igs are involved in mechanism of epithelial ovarian cancer cell immune escape mechanisms and clues to the biological treatment of Igs for the targets in epithelial ovarian cancer cells
2 FOXP3 expression in epithelial ovarian cancer cells
CD4+CD25+ regulatory T cells (Treg) is the body to“active”approach to maintaining stability in autoimmune channels can inhibit inappropriate immune response, immune response can limit the scope, extent and time , while maintaining its own stability and the prevention of autoimmune diseases and transplant rejection control play very important role in the protection. CD4+CD25+ Treg cells suppress the immune system in different types of cell differentiation and effector functions: conventional CD4+ and CD8+ T lymphocytes , NKT cells, B cells, dendritic cells and monocytes / macrophages. However, recent studies have found in the tumor micro-environment in the CD4+CD25+ Treg cells increased significantly, and inhibit tumor immune effect. Fork-like transcription factor FOXP3 is the first immunosuppressive cells, CD4+CD25+ Treg development in the thymus, peripheral maintenance of the expression and function of an important regulator of genes that will enable primary CD4+CD25- T cells into CD4+CD25+ Treg. In 2001, Bnmkow foxp3 genes was reported for the first time studying the of sf mice. Sf mice is due to foxp3 gene DNA-binding domain containing the two base frameshift insertion, caused by client protein C deficiency and the forkhead domain of transcription can not be regulation. sf mice CD4+ T cell-mediated immunity imbalance, fatal disease of lymphocyte proliferation and with multiple organ infiltration, lymphocyte infiltration and organ non-specific IL-2, IL-4, IL-10, IFN-γ, etc. a large number of secreted cytokines. Homologous human FOXP3 gene mutations can cause human diseases of immune disorders, endocrine diseases, enteropathy, X chromosome-linked syndrome (IPEX), performance for the full immune disorders, associated with autoimmune endocrine diseases such as early onsetⅠtype diabetes and thyroiditis, in some cases accompanied by severe atopic atopy, including eczema, food allergy and eosinophilic inflammation.
Usually found that the immune effects of tumor cells such as CD4+ T cells, CD8+ T cells, NK cell proliferation and activity were of the lower inhibitory ability. Lower of immune response exists in the tumor micro-environment.In order to explore the local epithelial ovarian cancer-related immune mechanisms Participation, this study conducted the following experiment:
(1)Study of FOXP3 in ovarian epithelial carcinoma tissues Application of immunohistochemical staining method we detected FOXP3 expreession in 46 cases of epithelial ovarian cancer. 36 cases of epithelial ovarian cancer was detected in FOXP3 expression, FOXP3 staining was brown showed the positioning of the nucleus in cancer cells.
(2)Study of FOXP3 expression in epithelial ovarian carcinoma cell lines Detecting FOXP3 expression in CAOV3 in SKOV3 cells. Application of reverse transcription polymerase chain reaction (RT-PCR) we detected the expression of two cells’FOXP3 mRNA expressions, sequencing, sequence and open reading frame (ORF) of the ratio; Application of immunocytochemical staining FOXP3 protein in SKOV3 cells and CAOV3 cells.
The results of the two cells were detected in the expression of FOXP3 mRNA. In SKOV3 cells FOXP3 mRNA fragments were in the same sequence of the GeneBank FOXP3 mRNA; CAOV3 cells FOXP3 mRNA fragments have a mutation, resulting in a leucine into a phenylalanine; FOXP3 protein in SKOV3 cells located in the nucleus, and in CAOV3 cells located in cytoplasm.
(3)FOXP3-specific siRNA interference experiment Observation of the expression of FOXP3 mRNA expression and FOXP3 protein expression by flow cytometry in SKOV3 cells after siRNA interference 48,72,96,120 hours after siRNA interference,comparing with Non-silencing siRNA group.
The results showed that 48h after siRNA interference can effectively inhibit the expression of FOXP3 mRNA and inhibit the FOXP3 protein expression after interfere 48,72,96,120 hours in siRNA group than Non-silencing siRNA group. In this study, the following conclusions:
(1) Epithelial ovarian cancer cells to express FOXP3, may be of an important mechanism epithelial ovarian cancer cells escape immune effector cells’attack constantly proliferation, invasion and metastasis.
(2) Epithelial ovarian cancer cells can express FOXP3, may be one of important mechanism the increasing CD4+ CD25+ Treg cells in the location of epithelial ovarian cancer tissue.
In this study, we first the time demonstrate epithelial ovarian cancer and ovarian cancer cell lines can express transcription factor FOXP3, will provide important theoretical basis for reveal the tumor low immune inhibition mechanisms in the locations of epithelial ovarian cancer tissue and important clues for epithelial ovarian cancer immune therapy provide.
引文
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