【摘要】：人類表皮腫瘤主要包括脂溢性角化癥、癌前病變(鮑溫病及鮑溫樣丘疹病等)、基底細(xì)胞癌及鱗狀細(xì)胞癌等。脂溢性角化癥(SK)系一種良性增生性表皮腫瘤,甚少惡變。鮑溫病(BD)又稱原位鱗狀細(xì)胞癌,屬表皮內(nèi)癌,鱗狀上皮細(xì)胞呈高度不典型性增生,基底膜帶完整；鮑溫樣丘疹病(BP)的病理組織學(xué)改變類似于鮑溫病,但比鮑瘟病異形性�。欢呔鶠榘┣安∽�,有可能發(fā)展成鱗狀細(xì)胞癌�；准�(xì)胞癌(BCC)是最常見的皮膚惡性腫瘤,由鱗狀上皮基底細(xì)胞發(fā)生,癌巢主要由基底細(xì)胞樣癌細(xì)胞構(gòu)成,局部浸潤至深層真皮組織,幾乎不發(fā)生轉(zhuǎn)移,呈低度惡性經(jīng)過。鱗狀細(xì)胞癌(SCC)主要由鱗狀上皮發(fā)生,癌巢向下生長突破基底膜帶并侵入真皮,呈不規(guī)則團(tuán)塊狀或束條狀,其惡性程度較基底細(xì)胞癌高,發(fā)展較快,破壞也較大,甚至出現(xiàn)全身性轉(zhuǎn)移。迄今,腫瘤發(fā)生發(fā)展的機(jī)制尚未被完全闡明。近期有文獻(xiàn)報(bào)道,腫瘤發(fā)生和發(fā)展與局部炎癥反應(yīng),尤其是慢性、持續(xù)性炎癥相關(guān)。多數(shù)情況下,人類腫瘤局部一般并不伴隨有病原體感染,故內(nèi)源性因子可能是啟動(dòng)腫瘤局部炎癥反應(yīng)的關(guān)鍵。其中,損傷相關(guān)的分子模式(DAMP)成為關(guān)注的熱點(diǎn).由于腫瘤細(xì)胞快速增殖,血液和氧氣供應(yīng)不足,以及機(jī)體抗瘤免疫所致細(xì)胞毒效應(yīng),均可導(dǎo)致腫瘤細(xì)胞壞死,從而釋放某些細(xì)胞內(nèi)組分,繼而引發(fā)炎癥應(yīng)答。高遷移率族蛋白B1(HMGBl)是細(xì)胞核內(nèi)DNA結(jié)合蛋白,在細(xì)胞壞死或某些炎癥因子刺激下,HMGBl可被動(dòng)或主動(dòng)地釋放至細(xì)胞外液,演變?yōu)橹匾傺准?xì)胞因子,作為DAMP與Toll樣受體4(TLR4)等結(jié)合,啟動(dòng)相關(guān)信號途徑而激活核轉(zhuǎn)錄因子kB (NF-κB),誘導(dǎo)炎癥因子的表達(dá),促進(jìn)細(xì)胞增殖并增強(qiáng)細(xì)胞抗凋亡作用。本課題以良性腫瘤、癌前病變、低度惡性及高度惡性腫瘤等表皮腫瘤為研究對象,觀察HMGB1及其受體TLR4和NF-κB p65在不同表皮腫瘤組織中的表達(dá),在此基礎(chǔ)上分析彼此之間的相關(guān)性,探討HMGB1-TLR4通路相關(guān)的炎癥反應(yīng)與人類表皮腫瘤發(fā)生發(fā)展的關(guān)系及可能的生物學(xué)意義。1.HMGB1在各表皮腫瘤組織中的表達(dá)及其意義免疫組化(IHC)檢測顯示：多種人類表皮腫瘤組織上皮細(xì)胞間隙可檢出胞外HMGB1,而正常皮膚鱗狀上皮細(xì)胞間隙基本未能檢出HMGBl。IHC半定量計(jì)分評定結(jié)果的差異分析顯示：脂溢性角化癥組胞外HMGB1水平顯著高于正常皮膚組(p0.01)；脂溢性角化癥中HMGB1水平與癌前病變及鱗狀細(xì)胞癌相比無顯著性差異。該實(shí)驗(yàn)結(jié)果提示：HMGB1可能是介導(dǎo)表皮腫瘤局部炎癥反應(yīng)的啟動(dòng)因子之一。2.TLR4在各表皮腫瘤組織中的表達(dá)及其意義免疫組化檢測結(jié)果顯示：多種人類表皮腫瘤組織病變上皮細(xì)胞均不同程度表達(dá)TLR4,以胞膜表達(dá)為主；脂溢性角化癥及癌前病變組織中,TLR4主要表達(dá)于上皮基底細(xì)胞及棘細(xì)胞胞膜；基底細(xì)胞癌部分癌變上皮細(xì)胞膜可表達(dá)TLR4；鱗狀細(xì)胞癌幾乎全部癌變上皮細(xì)胞膜強(qiáng)表達(dá)TLR4；正常皮膚可見TLR4主要表達(dá)于鱗狀上皮基底細(xì)胞膜。IHC半定量計(jì)分評定結(jié)果的差異分析顯示：高度惡性鱗狀細(xì)胞癌病變上皮細(xì)胞TLR4表達(dá)顯著高于基底細(xì)胞癌、癌前病變、脂溢性角化癥及正常皮膚上皮細(xì)胞,差異具有統(tǒng)計(jì)學(xué)意義(p0.01)。該實(shí)驗(yàn)結(jié)果提示：TLR4信號通路可能參與表皮高度惡性腫瘤局部炎癥反應(yīng)。3. NF-κB p65在各表皮腫瘤組織中的表達(dá)及其意義免疫組化和Western blot檢測顯示：人類表皮腫瘤組織病變上皮細(xì)胞均表達(dá)p65,主要位于胞漿,胞核可見不同程度表達(dá)；正常皮膚鱗狀上皮細(xì)胞核基本未見p65表達(dá)。IHC半定量計(jì)分評定結(jié)果的差異分析顯示：病變鱗狀上皮細(xì)胞核內(nèi)p65水平均高于正常皮膚上皮細(xì)胞核；隨良性增生、癌前病變、低度惡性至高度惡性演變過程,上皮細(xì)胞核p65水平逐漸升高,差異具有統(tǒng)計(jì)學(xué)意義(p0.01)。該實(shí)驗(yàn)結(jié)果提示：隨著腫瘤惡性變,腫瘤局部炎癥反應(yīng)亦逐漸增強(qiáng)。四、相關(guān)性分析IHC半定量計(jì)分Spearman's秩相關(guān)分析顯示：各表皮腫瘤組織及正常皮膚上皮細(xì)胞核p65表達(dá)與上皮細(xì)胞TLR4的表達(dá)呈極顯著正相關(guān)性(p0.01)。結(jié)論1.HMGBl-TLR4-NF-κB通路及其介導(dǎo)的炎癥反應(yīng)可能是參與人類表皮腫瘤組織發(fā)生、發(fā)展的重要機(jī)制之一。2.隨著腫瘤惡性變,上皮細(xì)胞核p65水平逐漸升高,腫瘤局部炎癥反應(yīng)逐漸增強(qiáng)。3.HMGBl可能是介導(dǎo)表皮腫瘤局部炎癥反應(yīng)的啟動(dòng)因子之一。4.TLR4信號通路可能參與表皮高度惡性腫瘤局部炎癥反應(yīng)。5.NF-κB p65和TLR4在表皮高度惡性腫瘤中起到重要的作用,聯(lián)合檢測表皮腫瘤組織的上皮細(xì)胞核p65及上皮細(xì)胞TLR4對于表皮惡性腫瘤的診斷具有重要意義。
[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.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R739.5

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相關(guān)期刊論文 前1條

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本文編號：2207483