HMGB1、TLR4和NF-κB p65在人类表皮肿瘤组织中的表达及其意义
发布时间：2018-08-27 13:50
【摘要】：人类表皮肿瘤主要包括脂溢性角化症、癌前病变(鲍温病及鲍温样丘疹病等)、基底细胞癌及鳞状细胞癌等。脂溢性角化症(SK)系一种良性增生性表皮肿瘤,甚少恶变。鲍温病(BD)又称原位鳞状细胞癌,属表皮内癌,鳞状上皮细胞呈高度不典型性增生,基底膜带完整；鲍温样丘疹病(BP)的病理组织学改变类似于鲍温病,但比鲍瘟病异形性小；二者均为癌前病变,有可能发展成鳞状细胞癌。基底细胞癌(BCC)是最常见的皮肤恶性肿瘤,由鳞状上皮基底细胞发生,癌巢主要由基底细胞样癌细胞构成,局部浸润至深层真皮组织,几乎不发生转移,呈低度恶性经过。鳞状细胞癌(SCC)主要由鳞状上皮发生,癌巢向下生长突破基底膜带并侵入真皮,呈不规则团块状或束条状,其恶性程度较基底细胞癌高,发展较快,破坏也较大,甚至出现全身性转移。迄今,肿瘤发生发展的机制尚未被完全阐明。近期有文献报道,肿瘤发生和发展与局部炎症反应,尤其是慢性、持续性炎症相关。多数情况下,人类肿瘤局部一般并不伴随有病原体感染,故内源性因子可能是启动肿瘤局部炎症反应的关键。其中,损伤相关的分子模式(DAMP)成为关注的热点.由于肿瘤细胞快速增殖,血液和氧气供应不足,以及机体抗瘤免疫所致细胞毒效应,均可导致肿瘤细胞坏死,从而释放某些细胞内组分,继而引发炎症应答。高迁移率族蛋白B1(HMGBl)是细胞核内DNA结合蛋白,在细胞坏死或某些炎症因子刺激下,HMGBl可被动或主动地释放至细胞外液,演变为重要促炎细胞因子,作为DAMP与Toll样受体4(TLR4)等结合,启动相关信号途径而激活核转录因子kB (NF-κB),诱导炎症因子的表达,促进细胞增殖并增强细胞抗凋亡作用。本课题以良性肿瘤、癌前病变、低度恶性及高度恶性肿瘤等表皮肿瘤为研究对象,观察HMGB1及其受体TLR4和NF-κB p65在不同表皮肿瘤组织中的表达,在此基础上分析彼此之间的相关性,探讨HMGB1-TLR4通路相关的炎症反应与人类表皮肿瘤发生发展的关系及可能的生物学意义。1.HMGB1在各表皮肿瘤组织中的表达及其意义免疫组化(IHC)检测显示：多种人类表皮肿瘤组织上皮细胞间隙可检出胞外HMGB1,而正常皮肤鳞状上皮细胞间隙基本未能检出HMGBl。IHC半定量计分评定结果的差异分析显示：脂溢性角化症组胞外HMGB1水平显著高于正常皮肤组(p0.01)；脂溢性角化症中HMGB1水平与癌前病变及鳞状细胞癌相比无显著性差异。该实验结果提示：HMGB1可能是介导表皮肿瘤局部炎症反应的启动因子之一。2.TLR4在各表皮肿瘤组织中的表达及其意义免疫组化检测结果显示：多种人类表皮肿瘤组织病变上皮细胞均不同程度表达TLR4,以胞膜表达为主；脂溢性角化症及癌前病变组织中,TLR4主要表达于上皮基底细胞及棘细胞胞膜；基底细胞癌部分癌变上皮细胞膜可表达TLR4；鳞状细胞癌几乎全部癌变上皮细胞膜强表达TLR4；正常皮肤可见TLR4主要表达于鳞状上皮基底细胞膜。IHC半定量计分评定结果的差异分析显示：高度恶性鳞状细胞癌病变上皮细胞TLR4表达显著高于基底细胞癌、癌前病变、脂溢性角化症及正常皮肤上皮细胞,差异具有统计学意义(p0.01)。该实验结果提示：TLR4信号通路可能参与表皮高度恶性肿瘤局部炎症反应。3. NF-κB p65在各表皮肿瘤组织中的表达及其意义免疫组化和Western blot检测显示：人类表皮肿瘤组织病变上皮细胞均表达p65,主要位于胞浆,胞核可见不同程度表达；正常皮肤鳞状上皮细胞核基本未见p65表达。IHC半定量计分评定结果的差异分析显示：病变鳞状上皮细胞核内p65水平均高于正常皮肤上皮细胞核；随良性增生、癌前病变、低度恶性至高度恶性演变过程,上皮细胞核p65水平逐渐升高,差异具有统计学意义(p0.01)。该实验结果提示：随着肿瘤恶性变,肿瘤局部炎症反应亦逐渐增强。四、相关性分析IHC半定量计分Spearman's秩相关分析显示：各表皮肿瘤组织及正常皮肤上皮细胞核p65表达与上皮细胞TLR4的表达呈极显著正相关性(p0.01)。结论1.HMGBl-TLR4-NF-κB通路及其介导的炎症反应可能是参与人类表皮肿瘤组织发生、发展的重要机制之一。2.随着肿瘤恶性变,上皮细胞核p65水平逐渐升高,肿瘤局部炎症反应逐渐增强。3.HMGBl可能是介导表皮肿瘤局部炎症反应的启动因子之一。4.TLR4信号通路可能参与表皮高度恶性肿瘤局部炎症反应。5.NF-κB p65和TLR4在表皮高度恶性肿瘤中起到重要的作用,联合检测表皮肿瘤组织的上皮细胞核p65及上皮细胞TLR4对于表皮恶性肿瘤的诊断具有重要意义。
[Abstract]:Human epidermal tumors include seborrheic keratosis, precancerous lesions (Bowen's disease, Bowenoid papulosis, etc.), basal cell carcinoma, squamous cell carcinoma, etc. Seborrheic keratosis (SK) is a benign proliferative epidermal tumor with few malignant changes. Basal cell carcinoma (BCC) is the most common skin malignancy, occurring from the basal cells of squamous epithelium, and the nests are mainly fine basal cells. Squamous cell carcinoma (SCC) mainly develops from squamous epithelium. The nests grow downward and break through the basement membrane band and invade the dermis. They are irregular clumps or bundles. The degree of malignancy of SCC is higher than that of basal cell carcinoma. Up to now, the mechanism of tumorigenesis and development has not been fully elucidated. Recently, it has been reported that tumorigenesis and development are related to local inflammation, especially chronic and persistent inflammation. Damage-related molecular models (DAMPs) are the key to local inflammation. Rapid proliferation of tumor cells, insufficient supply of blood and oxygen, and cytotoxic effects of anti-tumor immunity can lead to necrosis of tumor cells and release some intracellular components, leading to inflammation. Group B1 (HMGBl) is a DNA-binding protein in the nucleus. Under the stimulation of cell necrosis or some inflammatory factors, HMGBl can be released passively or actively into extracellular fluid and evolve into an important pro-inflammatory cytokine. As DAMP binds to Toll-like receptor 4 (TLR4), it activates nuclear transcription factor kB (NF-kappa B) and induces inflammatory factors. The aim of this study is to investigate the expression of HMGB1 and its receptors TLR4 and NF-kappa B p65 in different epidermal tumors, and to analyze the correlation between them. Expression of HMGB1 in various epidermal tumors and its significance Immunohistochemical (IHC) detection showed that extracellular HMGB1 could be detected in the epithelial spaces of various human epidermal tumors, while extracellular HMGB1 could be detected in normal skin squamous epithelial cells. The difference analysis of the semi-quantitative score of HMGBl.IHC showed that the level of extracellular HMGB1 in seborrheic keratosis group was significantly higher than that in normal skin group (p0.01); the level of HMGB1 in seborrheic keratosis was not significantly different from that in precancerous lesions and squamous cell carcinoma. Expression of TLR4 in various epidermal neoplasms and its significance Immunohistochemical staining showed that TLR4 was mainly expressed on the membrane of epithelial cells in various human epidermal neoplasms, and TLR4 was mainly expressed in the basal epithelium of seborrheic keratosis and precancerous lesions. TLR4 was strongly expressed in almost all cancerous epithelial cell membranes of squamous cell carcinoma. TLR4 was mainly expressed in squamous epithelial basement cell membranes of normal skin. Difference analysis of IHC semi-quantitative scoring results showed that highly malignant squamous cell carcinomas were found. The expression of TLR4 in epithelial cells was significantly higher than that in basal cell carcinoma, precancerous lesions, seborrheic keratosis and normal skin epithelial cells (p0.01). The results suggest that TLR4 signaling pathway may be involved in the local inflammatory response of epidermal malignancies. 3. The expression and significance of NF-kappa B p65 in various epidermal tumors. The results of immunohistochemistry and Western blot showed that p65 was mainly expressed in the cytoplasm and nucleus of human epidermal neoplasms, but not in the nucleus of normal skin squamous epithelial cells. The level of p65 in the epithelial cell nucleus increased gradually with benign hyperplasia, precancerous lesion, low-grade malignancy to high-grade malignancy (p0.01). The results showed that the local inflammatory response of the tumor was also gradually enhanced with malignant transformation of the tumor. 4. Correlation analysis of IHC semidefinite. Quantitative Spearman's rank correlation analysis showed that the expression of p65 in the nuclei of epidermal tumors and normal skin epithelial cells was positively correlated with the expression of TLR4 in epithelial cells (p0.01). Conclusion 1. HMGBl-TLR4-NF-kappa B pathway and its mediated inflammatory response may be one of the important mechanisms involved in the occurrence and development of human epidermal tumors. HMGBl may be one of the factors that mediate the local inflammatory response of epidermal tumors. 4. TLR4 signaling pathway may participate in the local inflammatory response of highly malignant epidermal tumors. 5. NF-kappa B p65 and TLR4 may play a role in high malignant epithelial tumors. It is important to detect p65 and TLR4 in epidermal tumor tissues for the diagnosis of epidermal malignancies.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R739.5
本文编号：2207483
[Abstract]:Human epidermal tumors include seborrheic keratosis, precancerous lesions (Bowen's disease, Bowenoid papulosis, etc.), basal cell carcinoma, squamous cell carcinoma, etc. Seborrheic keratosis (SK) is a benign proliferative epidermal tumor with few malignant changes. Basal cell carcinoma (BCC) is the most common skin malignancy, occurring from the basal cells of squamous epithelium, and the nests are mainly fine basal cells. Squamous cell carcinoma (SCC) mainly develops from squamous epithelium. The nests grow downward and break through the basement membrane band and invade the dermis. They are irregular clumps or bundles. The degree of malignancy of SCC is higher than that of basal cell carcinoma. Up to now, the mechanism of tumorigenesis and development has not been fully elucidated. Recently, it has been reported that tumorigenesis and development are related to local inflammation, especially chronic and persistent inflammation. Damage-related molecular models (DAMPs) are the key to local inflammation. Rapid proliferation of tumor cells, insufficient supply of blood and oxygen, and cytotoxic effects of anti-tumor immunity can lead to necrosis of tumor cells and release some intracellular components, leading to inflammation. Group B1 (HMGBl) is a DNA-binding protein in the nucleus. Under the stimulation of cell necrosis or some inflammatory factors, HMGBl can be released passively or actively into extracellular fluid and evolve into an important pro-inflammatory cytokine. As DAMP binds to Toll-like receptor 4 (TLR4), it activates nuclear transcription factor kB (NF-kappa B) and induces inflammatory factors. The aim of this study is to investigate the expression of HMGB1 and its receptors TLR4 and NF-kappa B p65 in different epidermal tumors, and to analyze the correlation between them. Expression of HMGB1 in various epidermal tumors and its significance Immunohistochemical (IHC) detection showed that extracellular HMGB1 could be detected in the epithelial spaces of various human epidermal tumors, while extracellular HMGB1 could be detected in normal skin squamous epithelial cells. The difference analysis of the semi-quantitative score of HMGBl.IHC showed that the level of extracellular HMGB1 in seborrheic keratosis group was significantly higher than that in normal skin group (p0.01); the level of HMGB1 in seborrheic keratosis was not significantly different from that in precancerous lesions and squamous cell carcinoma. Expression of TLR4 in various epidermal neoplasms and its significance Immunohistochemical staining showed that TLR4 was mainly expressed on the membrane of epithelial cells in various human epidermal neoplasms, and TLR4 was mainly expressed in the basal epithelium of seborrheic keratosis and precancerous lesions. TLR4 was strongly expressed in almost all cancerous epithelial cell membranes of squamous cell carcinoma. TLR4 was mainly expressed in squamous epithelial basement cell membranes of normal skin. Difference analysis of IHC semi-quantitative scoring results showed that highly malignant squamous cell carcinomas were found. The expression of TLR4 in epithelial cells was significantly higher than that in basal cell carcinoma, precancerous lesions, seborrheic keratosis and normal skin epithelial cells (p0.01). The results suggest that TLR4 signaling pathway may be involved in the local inflammatory response of epidermal malignancies. 3. The expression and significance of NF-kappa B p65 in various epidermal tumors. The results of immunohistochemistry and Western blot showed that p65 was mainly expressed in the cytoplasm and nucleus of human epidermal neoplasms, but not in the nucleus of normal skin squamous epithelial cells. The level of p65 in the epithelial cell nucleus increased gradually with benign hyperplasia, precancerous lesion, low-grade malignancy to high-grade malignancy (p0.01). The results showed that the local inflammatory response of the tumor was also gradually enhanced with malignant transformation of the tumor. 4. Correlation analysis of IHC semidefinite. Quantitative Spearman's rank correlation analysis showed that the expression of p65 in the nuclei of epidermal tumors and normal skin epithelial cells was positively correlated with the expression of TLR4 in epithelial cells (p0.01). Conclusion 1. HMGBl-TLR4-NF-kappa B pathway and its mediated inflammatory response may be one of the important mechanisms involved in the occurrence and development of human epidermal tumors. HMGBl may be one of the factors that mediate the local inflammatory response of epidermal tumors. 4. TLR4 signaling pathway may participate in the local inflammatory response of highly malignant epidermal tumors. 5. NF-kappa B p65 and TLR4 may play a role in high malignant epithelial tumors. It is important to detect p65 and TLR4 in epidermal tumor tissues for the diagnosis of epidermal malignancies.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R739.5
【参考文献】
相关期刊论文 前1条
1 刘辉,姚咏明,董月青,于燕,盛志勇;高迁移率族蛋白B1诱导巨噬细胞Janus激酶/信号转导及转录激活子通路活化的研究[J];中国危重病急救医学;2004年10期
，本文编号：2207483
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