mTOR/P70S6K信号通路在病理性瘢痕中的表达及意义
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摘要
目的：
病理性瘢痕(pathologic scar, PS)主要包括瘢痕疙瘩(keloid, K)和增生性瘢痕(hypertrophic scar, HS)。临床上可表现为痛、痒等感觉异常,肿瘤样生长,甚至伴有不同程度的功能障碍。其在组织学上主要表现为细胞外基质的过度聚集以及成纤维细胞的过度增生,而成纤维细胞增生过度或凋亡不足则是病理性瘢痕形成的重要生物学基础。
哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)属于丝氨酸/苏氨酸蛋白激酶,一方面可调控基因转录、蛋白质翻译和细胞生长周期；另一方面是磷酯酰肌醇3-激酶(phosphatidylinositol 3-kina-ses, PI3K)/蛋白激酶B(protein kinase B, Akt/PKB)信号通路的关键因子,并能活化下游底物,发挥生物学活性,处于细胞生长调控的中心环节。作为mTOR的直接底物,核糖体40S小亚基S6蛋白激酶(70-kDa ribosomal protein S6 kinase, P70S6K)可以刺激核糖体合成,加速mRNA翻译过程,缩短细胞增殖周期,从而促进细胞生长。既往对mTOR及其上游蛋白如P13K和Akt等的研究证实其在成纤维细胞增殖和瘢痕形成过程中发挥一定作用,而：mTOR/P70S6K信号通路和病理性瘢痕关系的研究则报道较少。磷酸化mTOR和磷酸化P70S6K(p-mTOR和p-P70S6K)分别是mTOR和P70S6K在体内的活性表现形式,实验利用免疫组化SP法通过对p-mTOR和p-P70S6K在病理性瘢痕中表达的检测,探讨mTOR/P70S6K信号通路在病理性瘢痕形成中的作用。
材料与方法：
实验标本来自2008.7～2010.3郑州大学第一附属医院整形外科住院患者。其中,瘢痕疙瘩20例,男9例,女11例,年龄3.5岁～25岁,病程6个月～12年,分别取材于耳部、胸部、腋窝部及左上肢部；增生性瘢痕20例,男12例,女8例,年龄7.5岁～19岁,病程9个月～7年,分别取材于面颈部、肩背部、腋窝部及上肢部；非病理性瘢痕20例,男13例,女7例,年龄7岁～56岁,病程11个月～18年,取材于面颈部、双上肢、右小腿及右下腹部；正常皮肤取自美容手术切除和全厚皮片移植剩余的全厚皮,共20例,男11例,女9例,年龄5.5岁～46岁,取材于眼睑、上臂内侧、腹部及脐周。所有患者均无皮肤疾病、结缔组织病、传染病、恶性肿瘤和其他重要脏器疾病,术前无放疗、激光治疗及免疫治疗史。运用免疫组织化学SP法,探讨p-mTOR和p-P70S6K在瘢痕疙瘩、增生性瘢痕、非病理性瘢痕及正常皮肤组织中的表达水平以及病理性瘢痕组织中p-mTOR和p-P70S6K的表达关系。
统计方法采用SPSS16.0软件对数据进行处理,各组织中蛋白表达阳性率采用χ2检验、χ2分割检验,病理性瘢痕中p-mTOR和p-P70S6K的表达关系采用关联性分析。检验水准α=0.05。
结果：
1. p-mTOR在病理性瘢痕中主要表达于成纤维细胞胞质及部分胞核中,呈棕黄色。非病理性瘢痕少量表达,正常皮肤组织中偶见少数细胞呈阳性反应。
2. P70S6K在病理性瘢痕中主要表达于成纤维细胞胞质及部分胞核中,呈棕黄色。非病理性瘢痕少量表达,正常皮肤组织中偶见少数细胞呈阳性反应。
3.病理性瘢痕组织中p-mTOR表达阳性率为75.00%,显著高于非病理性瘢痕的20.00%和正常皮肤组织的10.00%,经统计学检验,差异有显著性意义(P<0.0167)
4.病理性瘢痕组织中p-P70S6K表达阳性率为72.50%,显著高于非病理性瘢痕的10.00%和正常皮肤组织的5.00%,经统计学检验,差异有显著性意义(P<0.0167)
5.相关性分析显示,病理性瘢痕组织中p-mTOR和p-P70S6K的表达呈正相关(r=0.482,P<0.05)。
结论：
1. p-mTOR在病理性瘢痕中的表达明显高于非病理瘢痕及正常皮肤,它的高表达可能通过某种细胞信号转导途径增加能量代谢,促进蛋白质合成,致使细胞肥大,促进成纤维细胞的增殖和生长,抑制成纤维细胞的凋亡,从而促进病理性瘢痕的形成与发展过程。
2. p-P70S6K在病理性瘢痕中的高表达可能通过其调控细胞周期、促进核糖体生物合成等方式,刺激成纤维细胞生长和增殖,参与病理性瘢痕的形成与发展。
3. p-mTOR和p-P70S6K在病理性瘢痕中的表达呈正相关,二者在参与病理性瘢痕形成和发展过程中可能具有协同作用。
Objectives:
Pathologic scar (PS) mainly includes keloid (K) and hypertrophic scar (HS). The general performance is pain, pruritic, tumor-like growth, even with varying degrees of dysfunction in clinic manifestation. It is ariseed excessive accumulation of extracellular matrix and excessive fibroblast proliferation in histology manifestation, while the proliferation of fibroblasts from excessive or insufficient apoptosis is the important biological foundation for the formation of pathologic scar.
Mammalian target of rapamycin (mTOR) is a kind of serine/threonine protein kinase. On the one hand, it can regulate gene transcription, protein translation and cell growth cycle. On the other hand, it is a key factor of signaling pathway of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt/PKB) and the key step of regulation of cell growth. It can activate downstream substrates and exert biological activity. As the direct substrate of mTOR,70-kDa ribosomal protein S6 kinase(P70S6K) can stimulate the ribosome synthesis, accelerate the translation process of mRNA, shorten the cell cycle, and increase the rate of cell growth, so that promot the cell growth. In the past few years, the study of mTOR and its upstream proteins such as PI3K, Akt and other studies confirmed that it plays an important role in the fibroblast proliferation and pathologic scar formation, but the study of the relationship between mTOR/P70S6K signaling pathway and pathological scar is rarely reported. Phosphorylated mTOR and phosphorylated P70S6K (p-mTOR and p-P70S6K) are the activated form of mTOR and P70S6K in vivo, p-mTOR and p-P70S6K expression in the pathological scar were detected for the research with immunohistochemical SP method, and discuss the role of mTOR/P70S6K signaling pathway in the formation of pathological scar role.
Materials and methods:
The samples were collected from Department of Plastic Surgery, the First Affiliated Hospital of Zhengzhou University from July,2008 to March,2005. There were 20 cases of keloid,9 males and 11 females, aged from 3.5 years old to 25 years old, with the course of disease from 6months to 12 years. The samples were respectively harvested from the ear, chest, armpit, and the left upper limb. There were 20 cases of hypertrophic scar,12 males and 8 females, aged from 7.5 years old to 19 years old, with the course of disease from 9 months to 7 years. The samples were harvested from face and neck, shoulder, armpit and upper limb. There were 20 cases of non-hypertrophic scar,13 males and 7 females, aged from 7 years old to 56 years old, with the course of disease from 11 months to 18 years. The samples were harvested from the face and neck, upper limbs, right leg and right lower abdomen, there were 20 cases of normal skin,11 males and 9 females, aged from 5.5 years old to 46 years old. The samples were harvested from the eyelids, inside upper arm, abdomen and peri-umbilicus, which were remanent at the cosmetic surgery and full-thickness skin graft. All the patients do not have skin diseases, connective tissue diseases, infectious diseases, cancer or other major organ disease, and there was no history of radiotherapy, laser therapy or immunotherapy preoperation. Immunohistochemical SP method was adopt to study the expression of p-mTOR and p-P70S6K in the keloid, hypertrophic scar, non-hypertrophic scar and normal skin tissue, and the relationship between the expression of p-mTOR and p-P70S6K in pathological scar tissue.
On the base of the above researches, the experiment data are analyzed with statistical package for the social 16.0(SPSS16.0) software package. The positive rate of tissue protein list was analyzed with x2 inspection and analysis of variance. Study on the relationship between the expression of p-mTOR and p-P70S6K in pathological scar tissue. A value less than 0.05 was considered as significance.
Results:
1. p-mTOR mainly expressed in the fibroblasts cytoplasm and some nuclei with brownish yellow in pathological scar, a small amount of non-expression in hypertrophic scar. It was expressed occasionally in the normal skin.
2. P70S6K mainly expressed in the fibroblasts cytoplasm and some nuclei with brownish yellow in pathological scar, a small amount of non-expression in hypertrophic scar. It was expressed occasionally in the normal skin.
3. The p-mTOR expression rate (75.00%) in Pathologic scar tissue was significantly higher than non-hypertrophic scar (20.00%) and normal skin (10.00%), the difference was significant (P< 0.0167)
4. The p-P70S6K expression rate (72.50%) in Pathologic scar tissue was significantly higher than non-hypertrophic scar (10.00%) and normal skin (5.00%), the difference was significant (P< 0.0167)
5. Correlation analysis showed that p-mTOR and p-P70S6K expression was positively correlated in pathologic scar tissue (r= 0.482, P< 0.05).
Conclusions:
1. The p-mTOR expression rate in pathological scar was significantly higher than non-pathological scar and normal skin. Its high expression may be through some kind of cell signal transduction pathway to increase energy metabolism, promote protein synthesis and cell hypertrophied, promote fibroblast cell proliferation, inhibit the apoptosis of skin fibroblasts, which plays an important role in the formation and development of pathological scar.
2. The p-P70S6K expression rate in pathological scar was significantly higher, which may promote fibroblast cell proliferation by the way of regulating and controlling cell cycle, and ribosome biogenesis. So that it plays an important role in the formation and development of pathological scar.
3. p-mTOR and p-P70S6K expression was positively correlated in pathologic scar tissue, which may play a synergistic effect in pathological scar formation and development.
病理性瘢痕(pathologic scar, PS)主要包括瘢痕疙瘩(keloid, K)和增生性瘢痕(hypertrophic scar, HS)。临床上可表现为痛、痒等感觉异常,肿瘤样生长,甚至伴有不同程度的功能障碍。其在组织学上主要表现为细胞外基质的过度聚集以及成纤维细胞的过度增生,而成纤维细胞增生过度或凋亡不足则是病理性瘢痕形成的重要生物学基础。
哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)属于丝氨酸/苏氨酸蛋白激酶,一方面可调控基因转录、蛋白质翻译和细胞生长周期；另一方面是磷酯酰肌醇3-激酶(phosphatidylinositol 3-kina-ses, PI3K)/蛋白激酶B(protein kinase B, Akt/PKB)信号通路的关键因子,并能活化下游底物,发挥生物学活性,处于细胞生长调控的中心环节。作为mTOR的直接底物,核糖体40S小亚基S6蛋白激酶(70-kDa ribosomal protein S6 kinase, P70S6K)可以刺激核糖体合成,加速mRNA翻译过程,缩短细胞增殖周期,从而促进细胞生长。既往对mTOR及其上游蛋白如P13K和Akt等的研究证实其在成纤维细胞增殖和瘢痕形成过程中发挥一定作用,而：mTOR/P70S6K信号通路和病理性瘢痕关系的研究则报道较少。磷酸化mTOR和磷酸化P70S6K(p-mTOR和p-P70S6K)分别是mTOR和P70S6K在体内的活性表现形式,实验利用免疫组化SP法通过对p-mTOR和p-P70S6K在病理性瘢痕中表达的检测,探讨mTOR/P70S6K信号通路在病理性瘢痕形成中的作用。
材料与方法：
实验标本来自2008.7～2010.3郑州大学第一附属医院整形外科住院患者。其中,瘢痕疙瘩20例,男9例,女11例,年龄3.5岁～25岁,病程6个月～12年,分别取材于耳部、胸部、腋窝部及左上肢部；增生性瘢痕20例,男12例,女8例,年龄7.5岁～19岁,病程9个月～7年,分别取材于面颈部、肩背部、腋窝部及上肢部；非病理性瘢痕20例,男13例,女7例,年龄7岁～56岁,病程11个月～18年,取材于面颈部、双上肢、右小腿及右下腹部；正常皮肤取自美容手术切除和全厚皮片移植剩余的全厚皮,共20例,男11例,女9例,年龄5.5岁～46岁,取材于眼睑、上臂内侧、腹部及脐周。所有患者均无皮肤疾病、结缔组织病、传染病、恶性肿瘤和其他重要脏器疾病,术前无放疗、激光治疗及免疫治疗史。运用免疫组织化学SP法,探讨p-mTOR和p-P70S6K在瘢痕疙瘩、增生性瘢痕、非病理性瘢痕及正常皮肤组织中的表达水平以及病理性瘢痕组织中p-mTOR和p-P70S6K的表达关系。
统计方法采用SPSS16.0软件对数据进行处理,各组织中蛋白表达阳性率采用χ2检验、χ2分割检验,病理性瘢痕中p-mTOR和p-P70S6K的表达关系采用关联性分析。检验水准α=0.05。
结果：
1. p-mTOR在病理性瘢痕中主要表达于成纤维细胞胞质及部分胞核中,呈棕黄色。非病理性瘢痕少量表达,正常皮肤组织中偶见少数细胞呈阳性反应。
2. P70S6K在病理性瘢痕中主要表达于成纤维细胞胞质及部分胞核中,呈棕黄色。非病理性瘢痕少量表达,正常皮肤组织中偶见少数细胞呈阳性反应。
3.病理性瘢痕组织中p-mTOR表达阳性率为75.00%,显著高于非病理性瘢痕的20.00%和正常皮肤组织的10.00%,经统计学检验,差异有显著性意义(P<0.0167)
4.病理性瘢痕组织中p-P70S6K表达阳性率为72.50%,显著高于非病理性瘢痕的10.00%和正常皮肤组织的5.00%,经统计学检验,差异有显著性意义(P<0.0167)
5.相关性分析显示,病理性瘢痕组织中p-mTOR和p-P70S6K的表达呈正相关(r=0.482,P<0.05)。
结论：
1. p-mTOR在病理性瘢痕中的表达明显高于非病理瘢痕及正常皮肤,它的高表达可能通过某种细胞信号转导途径增加能量代谢,促进蛋白质合成,致使细胞肥大,促进成纤维细胞的增殖和生长,抑制成纤维细胞的凋亡,从而促进病理性瘢痕的形成与发展过程。
2. p-P70S6K在病理性瘢痕中的高表达可能通过其调控细胞周期、促进核糖体生物合成等方式,刺激成纤维细胞生长和增殖,参与病理性瘢痕的形成与发展。
3. p-mTOR和p-P70S6K在病理性瘢痕中的表达呈正相关,二者在参与病理性瘢痕形成和发展过程中可能具有协同作用。
Objectives:
Pathologic scar (PS) mainly includes keloid (K) and hypertrophic scar (HS). The general performance is pain, pruritic, tumor-like growth, even with varying degrees of dysfunction in clinic manifestation. It is ariseed excessive accumulation of extracellular matrix and excessive fibroblast proliferation in histology manifestation, while the proliferation of fibroblasts from excessive or insufficient apoptosis is the important biological foundation for the formation of pathologic scar.
Mammalian target of rapamycin (mTOR) is a kind of serine/threonine protein kinase. On the one hand, it can regulate gene transcription, protein translation and cell growth cycle. On the other hand, it is a key factor of signaling pathway of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt/PKB) and the key step of regulation of cell growth. It can activate downstream substrates and exert biological activity. As the direct substrate of mTOR,70-kDa ribosomal protein S6 kinase(P70S6K) can stimulate the ribosome synthesis, accelerate the translation process of mRNA, shorten the cell cycle, and increase the rate of cell growth, so that promot the cell growth. In the past few years, the study of mTOR and its upstream proteins such as PI3K, Akt and other studies confirmed that it plays an important role in the fibroblast proliferation and pathologic scar formation, but the study of the relationship between mTOR/P70S6K signaling pathway and pathological scar is rarely reported. Phosphorylated mTOR and phosphorylated P70S6K (p-mTOR and p-P70S6K) are the activated form of mTOR and P70S6K in vivo, p-mTOR and p-P70S6K expression in the pathological scar were detected for the research with immunohistochemical SP method, and discuss the role of mTOR/P70S6K signaling pathway in the formation of pathological scar role.
Materials and methods:
The samples were collected from Department of Plastic Surgery, the First Affiliated Hospital of Zhengzhou University from July,2008 to March,2005. There were 20 cases of keloid,9 males and 11 females, aged from 3.5 years old to 25 years old, with the course of disease from 6months to 12 years. The samples were respectively harvested from the ear, chest, armpit, and the left upper limb. There were 20 cases of hypertrophic scar,12 males and 8 females, aged from 7.5 years old to 19 years old, with the course of disease from 9 months to 7 years. The samples were harvested from face and neck, shoulder, armpit and upper limb. There were 20 cases of non-hypertrophic scar,13 males and 7 females, aged from 7 years old to 56 years old, with the course of disease from 11 months to 18 years. The samples were harvested from the face and neck, upper limbs, right leg and right lower abdomen, there were 20 cases of normal skin,11 males and 9 females, aged from 5.5 years old to 46 years old. The samples were harvested from the eyelids, inside upper arm, abdomen and peri-umbilicus, which were remanent at the cosmetic surgery and full-thickness skin graft. All the patients do not have skin diseases, connective tissue diseases, infectious diseases, cancer or other major organ disease, and there was no history of radiotherapy, laser therapy or immunotherapy preoperation. Immunohistochemical SP method was adopt to study the expression of p-mTOR and p-P70S6K in the keloid, hypertrophic scar, non-hypertrophic scar and normal skin tissue, and the relationship between the expression of p-mTOR and p-P70S6K in pathological scar tissue.
On the base of the above researches, the experiment data are analyzed with statistical package for the social 16.0(SPSS16.0) software package. The positive rate of tissue protein list was analyzed with x2 inspection and analysis of variance. Study on the relationship between the expression of p-mTOR and p-P70S6K in pathological scar tissue. A value less than 0.05 was considered as significance.
Results:
1. p-mTOR mainly expressed in the fibroblasts cytoplasm and some nuclei with brownish yellow in pathological scar, a small amount of non-expression in hypertrophic scar. It was expressed occasionally in the normal skin.
2. P70S6K mainly expressed in the fibroblasts cytoplasm and some nuclei with brownish yellow in pathological scar, a small amount of non-expression in hypertrophic scar. It was expressed occasionally in the normal skin.
3. The p-mTOR expression rate (75.00%) in Pathologic scar tissue was significantly higher than non-hypertrophic scar (20.00%) and normal skin (10.00%), the difference was significant (P< 0.0167)
4. The p-P70S6K expression rate (72.50%) in Pathologic scar tissue was significantly higher than non-hypertrophic scar (10.00%) and normal skin (5.00%), the difference was significant (P< 0.0167)
5. Correlation analysis showed that p-mTOR and p-P70S6K expression was positively correlated in pathologic scar tissue (r= 0.482, P< 0.05).
Conclusions:
1. The p-mTOR expression rate in pathological scar was significantly higher than non-pathological scar and normal skin. Its high expression may be through some kind of cell signal transduction pathway to increase energy metabolism, promote protein synthesis and cell hypertrophied, promote fibroblast cell proliferation, inhibit the apoptosis of skin fibroblasts, which plays an important role in the formation and development of pathological scar.
2. The p-P70S6K expression rate in pathological scar was significantly higher, which may promote fibroblast cell proliferation by the way of regulating and controlling cell cycle, and ribosome biogenesis. So that it plays an important role in the formation and development of pathological scar.
3. p-mTOR and p-P70S6K expression was positively correlated in pathologic scar tissue, which may play a synergistic effect in pathological scar formation and development.
引文
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