Clinical research on the expression of three vascular regulatory factors in different morphological regions of Marjolin ulcer and their relationship with angiogenesis
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摘要: 目的 探讨Marjolin溃疡不同形态区域中血管内皮生长因子(VEGF)、缺氧诱导因子1α(HIF-1α)和表皮生长因子受体(EGFR)的表达及其与血管生成的临床关系。 方法 笔者单位2012年1月—2017年12月收治符合入选标准的Marjolin溃疡患者92例[男56例、女36例,年龄(55±15)岁]、皮肤慢性非癌变溃疡患者100例[男59例、女41例,年龄(51±16)岁]、行其他皮肤相关手术治疗患者100例[男58例、女42例,年龄(52±15)岁],分别设为Marjolin溃疡组、慢性非癌变溃疡组、其他皮肤手术组。回顾性分析Marjolin溃疡组患者的病因、发病部位、溃疡直径、病程;取Marjolin溃疡组和慢性非癌变溃疡组患者溃疡组织标本、其他皮肤手术组患者术中切取组织周围附带的正常皮肤组织标本,采用免疫组织化学法检测各组织以及Marjolin溃疡组织周围正常皮肤区、溃疡区、上皮瘤样增生区、癌变区中VEGF、HIF-1α、EGFR、CD34的表达,计算阳性表达率及蛋白表达量。对数据行Pearson卡方检验、Mann-Whitney
U 检验、Bonferroni法检验、Bonferroni校正,对蛋白总表达量间的相关性进行Spearman相关分析。 结果 Marjolin溃疡组患者病因中烧伤占91.3%(84/92),44.6%(41/92)的患者肿瘤出现在下肢,62.0%(57/92)的患者皮肤表面溃疡直径为2.1~5.0 cm,病程超过20年者占75.0%(69/92)。慢性非癌变溃疡组患者溃疡组织VEGF、HIF-1α和EGFR阳性表达率分别为41.0%(41/100)、77.0%(77/100)、83.0%(83/100),显著高于其他皮肤手术组患者正常皮肤组织的12.0%(12/100)、45.0%(45/100)、67.0%(67/100),χ 2=21.589、21.522、6.827,P <0.01;Marjolin溃疡组患者溃疡组织VEGF、HIF-1α和EGFR阳性表达率分别为91.3%(84/92)、100.0%(92/92)、100.0%(92/92),显著高于慢性非癌变溃疡组和其他皮肤手术组患者相应组织(χ 2=53.372、24.772、17.159,120.543、72.777、36.661,P <0.01)。Marjolin溃疡组患者溃疡组织溃疡区、上皮瘤样增生区、癌变区VEGF阳性表达率明显高于周围正常皮肤区(χ 2=87.120、42.368、89.624,P <0.01),癌变区和溃疡区VEGF阳性表达率显著高于上皮瘤样增生区(χ 2=22.586、16.060,P <0.01)。Marjolin溃疡组患者溃疡组织溃疡区、上皮瘤样增生区和癌变区EGFR阳性表达率均显著高于周围正常皮肤区(χ 2=21.679、27.600、27.600,P <0.01),4个形态区域中HIF-1α阳性表达率相近(χ 2=3.008,P >0.05)。Marjolin溃疡组患者溃疡组织溃疡区、上皮瘤样增生区、癌变区VEGF和CD34蛋白表达量显著高于周围正常皮肤区(Z =-6.765、-6.819,-6.765、-6.640,-6.765、-6.819,P <0.01),上皮瘤样增生区VEGF和CD34蛋白表达量显著低于溃疡区(Z =-4.484、-5.266,P <0.01),癌变区VEGF和CD34蛋白表达量显著高于溃疡区(Z =-6.427、-6.723,P <0.01)和上皮瘤样增生区(Z =-6.427、-6.462,P <0.01)。Marjolin溃疡组患者溃疡组织溃疡区、上皮瘤样增生区、癌变区HIF-1α和EGFR蛋白表达量显著高于周围正常皮肤区(Z =-6.819、-6.393,-6.819、-6.393,-6.819、-6.393,P <0.01),溃疡区HIF-1α、EGFR蛋白表达量显著低于上皮瘤样增生区与癌变区(Z =-6.118、-5.638,-6.640、-6.393,P <0.01),癌变区HIF-1α和EGFR蛋白表达量显著高于上皮瘤样增生区(Z =-6.558、-6.819,P <0.01)。Marjolin溃疡组患者溃疡组织中VEGF、HIF-1α、EGFR蛋白总表达量分别与CD34蛋白总表达量呈显著正相关(r =0.772、0.415、0.502,P <0.01);EGFR和HIF-1α蛋白总表达量呈显著正相关(r =0.839,P <0.01),且分别与VEGF蛋白总表达量呈显著正相关(r =0.531、0.440,P <0.01)。 结论 Marjolin溃疡癌变区VEGF、HIF-1α和EGFR的表达最高,并且EGFR可能通过HIF-1α或者直接提高VEGF的表达,促进血管生成。-
关键词:
- 癌,鳞状细胞 /
- 血管内皮生长因子类 /
- 缺氧诱导因子1,α亚基 /
- 受体,表皮生长因子 /
- 血管 /
- Marjolin溃疡
Abstract: Objective To investigate the expressions of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 alpha (HIF-1α), and epidermal growth factor receptor (EGFR) in different morphological regions of Marjolin ulcer and their clinical relationship with angiogenesis. Methods From January 2012 to December 2017, the patients admitted to our hospital who met the inclusion criteria were selected, including 92 patients with Marjolin ulcer [56 males and 36 females, aged (55±15) years], 100 patients with chronic non-cancerous skin ulcer [59 males and 41 females, aged (51±16) years], and 100 patients performed with other skin-related surgery [58 males and 42 females, aged (52±15) years], and they were enrolled into Marjolin ulcer group (MU), chronic non-cancerous ulcer group (CNU), and other skin surgery group (OSS) respectively. The etiology, pathogenic site, ulcer diameter, and course of patients in group MU were retrospectively analyzed. Ulcer tissue specimens from patients of group MU and group CNU and specimens of normal skin tissue attached to the tissue resected during operation from patients of group OSS were collected. The expressions of VEGF, HIF-1α, EGFR, and CD34 in the above-mentioned tissue and the surrounding normal skin, ulcer, epitheliomatous hyperplasia, and canceration areas in Marjolin ulcer tissue were detected by immunohistochemical method, and the positive expression rate and protein expression level were calculated. Data were processed with Pearson chi-square test, Mann-WhitneyU test, Bonferroni method, and Bonferroni correction, and Spearman correlation analysis was used to analyze the relationship among the total protein expression levels. Results In group MU, burns accounted for 91.3% (84/92) of the causes of patients, 44.6% (41/92) of the patients had tumors in the lower extremities, 62.0% (57/92) of the patients had skin ulcer diameter of 2.1-5.0 cm, and 75.0% (69/92) of the patients had a course of disease of more than 20 years. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group CNU were 41.0% (41/100), 77.0% (77/100), and 83.0% (83/100), respectively, significantly higher than those of normal skin tissue of patients in group OSS [12.0% (12/100), 45.0% (45/100), and 67.0% (67/100),χ 2=21.589, 21.522, 6.827,P <0.01]. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group MU were 91.3% (84/92), 100.0% (92/92), and 100.0% (92/92), respectively, which were significantly higher than those in corresponding tissue of patients in group CNU and group OSS (χ 2=53.372, 24.772, 17.159; 120.543, 72.777, 36.661,P <0.01). In ulcer tissue of patients in group MU, the positive expression rates of VEGF in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area (χ 2=87.120, 42.368, 89.624,P <0.01); the positive expression rates of VEGF in canceration and ulcer areas were significantly higher than the rate in epitheliomatous hyperplasia area (χ 2=22.586, 16.060,P <0.01). In ulcer tissue of patients in group MU, the positive expression rates of EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area (χ 2=21.679, 27.600, 27.600,P <0.01), but the positive expression rates of HIF-1α in four morphological areas were similar (χ 2=3.008,P >0.05). In ulcer tissue of patients in group MU, the protein expression levels of VEGF and CD34 in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area (Z =-6.765, -6.819; -6.765, -6.640; -6.765, -6.819,P <0.01), the protein expression levels of VEGF and CD34 in epitheliomatous hyperplasia area were significantly lower than those in ulcer area (Z =-4.484, -5.266,P <0.01), and the protein expression levels of VEGF and CD34 in canceration area were significantly higher than those in ulcer area (Z =-6.427, -6.723,P <0.01) and epitheliomatous hyperplasia area (Z =-6.427, -6.462,P <0.01). In ulcer tissue of patients in group MU, the protein expression levels of HIF-1α and EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area (Z =-6.819, -6.393; -6.819, -6.393; -6.819, -6.393,P <0.01), the protein expression levels of HIF-1α and EGFR in ulcer area were significantly lower than those in epitheliomatous hyperplasia and canceration areas (Z =-6.118, -5.638; -6.640, -6.393,P <0.01), and the protein expression levels of HIF-1α and EGFR in canceration area were significantly higher than those in epitheliomatous hyperplasia area (Z =-6.558, -6.819,P <0.01). In ulcer tissue of patients in group MU, the total protein expression levels of VEGF, HIF-1α, and EGFR were significantly positively correlated with the total protein expression level of CD34 (r =0.772, 0.415, 0.502,P <0.01) respectively; the total protein expression level of EGFR was significantly positively correlated with that of HIF-1α (r =0.839,P <0.01), both of which were significantly positively correlated with the total protein expression level of VEGF (r =0.531, 0.440,P <0.01) respectively. Conclusions The expressions of VEGF, HIF-1α, and EGFR are the highest in Marjolin ulcer canceration area, and EGFR may promote angiogenesis through HIF-1α or directly increasing the expression of VEGF.
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