日光性角化病中TGFβ1/Smad信号通路作用机制的研究
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摘要
第一部分日光性角化病临床病理分析
目的：日光性角化病(AK)发病率逐年上升,并可进一步转化为鳞状细胞癌(SCC)。为提高临床诊断、防治水平及最大限度降低患病率及死亡率,完善高原地区AK流行病学资料,本研究就其临床、病理诊断方面的特点进行综合性分析。
方法：采用回顾性研究方法对昆明医科大学第一附属医院皮肤科2011年1月～2012年12月共2年间组织病理确诊、临床资料完整的52例AK患者资料进行分析。对HE组织切片进行观察,分析其病理特征,结果用SPSS17.0统计分析。
结果：2011至2012年间确诊AK52例,确诊AK占当年年病检量比率分别为0.49%和0.85%,占当年年门诊量比率分别为0.18‰和0.34‰,2012年占年门诊量比率比2011年上升(χ2=5.02,p=0.03)；其中男性18人,女性34人,男性：女性为1：1.89；发病年龄为45～82岁,其中<50岁4例(7.7%),50～59岁11例(21.2%),60～69岁17例(32.7%),70～79岁17例(32.7%),>80岁3例(5.8%),平均发病年龄为64.98±9.78,男性平均年龄(62.44±10.76)与女性(66.32±9.11)间无明显差异(t=-1.372,p=0.176)；患者以农民、建筑工人等室外工作者为主,共34例(65.3%),不同职业间的发病部位、发病年龄及病程无明显差别(p>0.05)；日光反应性皮肤分型Ⅲ型皮肤有27例(57.7%),Ⅳ型皮肤有25例(42.3%),不同皮肤类型间发病年龄及病程无明显差别(p>0.05)；AK皮损以红褐色、黑褐色斑丘疹伴鳞屑为主,共46例(88.5%),其中合并糜烂溃疡1例,仅黑色丘疹5例(9.6%),皮角样1例(1.9%),皮损全部分布于曝光部位,以面颊部(25例,48.1%)及颞部(23例,44.2%)多见,其次为鼻部(13例,25%)和额部(11例,21.2%),位于耳、颈及手背各1例(1.9%)；AK皮损以单发为主(71.2%),多于3处皮损患者有6例(11.5%),最多达到21处；皮损平均直径为17.87±9.92mm,不同发病部位皮损直径无明显差别(p>0.05)；病程平均为44.04±53.09月,其中男性平均病程为50.39±29.82,女性为40.68±62.16,男女发病平均病程比较无明显差异(p>0.05)；病理分型以肥厚型为主(51.9%),其次为萎缩型(21.2%)和色素型(15.4%),而棘层松解型(7.7%)和鲍温样型(3.8%)比较少见,其中2例合并SCC；52例病理确诊AK中,临床与病理诊断符合率仅为51.9%,其中误诊为脂溢性角化病13例,基底细胞癌2例,色素痣4例,寻常疣3例,皮角2例,角化棘皮瘤1例。
结论：1、确诊AK占年门诊量比率呈现上升趋势,应引起全社会的重视；2、AK多发于50岁以上女性的头面部曝光部位,以农民等户外工作者为主,与紫外线关系密切；3、AK临床表现多为红褐色、黑褐色斑丘疹伴鳞屑,平均病程为3.6年,以单发皮损为主,平均直径一般大于1cm;4、 AK病理分型以肥厚型为主,临床与病理诊断符合率不高,临床上容易误诊,应增加病检的适用范围,以免贻误病情,造成严重后果；5、AK向SCC转化概率高,应该早期诊断治疗。
第二部分日光性角化病中TGFβ1/Smad信号通路作用机制的研究
目的：AK发病率高,易向SCC转变,但发生发展机制不清。TGFβ1/Smad信号通路在皮肤癌早期抑制肿瘤生长,晚期却促进肿瘤侵袭转移,在AK中的作用机制未见报道。本研究探讨AK中TGFβ1/Smad信号通路的作用机制,阐明AK发生发展的机制。
方法：分别培养人AK组织块及原代细胞,分为三组,第一组对照组,第二组TGFβ1添加培养组,第三组SB431542添加培养组。活性调控处理48h后：①流式细胞术、Ki-67和Tunel染色检测AK细胞和组织增殖凋亡情况；②Real-timePCR和蛋白免疫印迹检测AK组织中TGFβ1/Smad信号通路TβRII和Smad2mRNA表达及蛋白磷酸化水平,检测培养组织块用于信号通路活性调控研究的可行性；③Real-time PCR和蛋白免疫印迹检测AK组织中p53、Fas和FasL mRNA及蛋白表达。
结果：①AK角质细胞培养12天后形态良好,呈典型的铺路石样改变。AK组织培养5天后,皮肤组织生长良好,未见大量细胞凋亡和死亡情况；②在TGFβ1添加培养后,AK角质形成细胞计数减少(99.80±6.06),Ki-67阳性细胞百分比(0.42±0.04)下降,AK组织中Ki-67阳性细胞百分比(3.90±0.24)减少(p<0.05)；③在AK组织块中,与对照组相比,TGFβ1添加后TβRI磷酸化水平(0.1858±0.0]07)增加；Smad2mRNA (0.01791±0.00080)表达增加,磷酸化水平(0.6112±0.0391)增加(p<0.05)。而SB431542添加后,TβRI磷酸化水平(0.0644±0.0053)减少(p6<0.05)；④在TGFβ1添加培养后,AK组织块中p53mRNA表达(0.00178±0.00010)增加,蛋白表达(0.1620±0.0155)增加,Fas蛋白表达(0.4004±0.0267)增加(p<0.05)。
结论：1.皮肤组织块可以作为信号通路活性调控模型。2. TGFβ1/Smad信号通路在AK中发挥抑制细胞增殖作用。3.TGFβ1/Smad信号通路通过促进p53和Fas表达而发挥抑制作用。
第三部分紫外线对日光性角化病中TGFβ1/Smad信号通路影响的研究
目的：紫外线促进日光性角化病(AK)发生及向鳞状细胞癌(SCC)进展,严重危害人民群众生命健康,TGFβ1/Smad信号通路在AK中发挥抑制作用,研究紫外线对TGFβ1/Smad信号通路的影响,阐明紫外线致癌靶点。
方法：分别培养AK和正常皮肤组织,分为四组,第一组为对照组,紫外线照射强度为0J/cm2,第二组为5J/cm2组,第三组为10J/cm2组,第四组为20J/cm2组。组织连续照射4天,继续培养24小时后取材,①Ki-67和Tunel染色检测AK组织增殖凋亡情况；②Real-time PCR和免疫组化检测AK组织中TGFβ1/Smad信号通路TGFβ1, TβRI, TβRII, Smad2, Smad3, Smad4和Smad7mRNA及蛋白表达。
结果：①紫外线照射后,与对照组比较(OJ/cm2组),Ki-67阳性细胞百分率(3.74±1.16)在正常皮肤20J/cm2组中表达减少,凋亡细胞在正常皮肤(39.34±8.73)和AK(25.76±5.99)20J/cm2组中明显增加(p<0.05)；②紫外线照射后,与对照组比较(OJ/cm2组),TGFβ1mRNA在正常皮肤10J/cm2(0.00821±0.00181)和20J/cm2(0.01040±0.00145)组表达增加,其蛋白在10J/cm2(0.1041±0.0064)和20J/cm2(0.1257±0.0135)组表达增加,在AK20J/cm2组其mRNA (0.00504±0.00122)和蛋白(0.0871±±0.0038)表达增加(P<0.05); TβRII mRNA (0.00119±0.00019)和蛋白(0.0366±0.0052)在正常皮肤20J/cm2组表达减少,在AK20J/cm2组其mRNA (0.00073±0.00029),在10J/cm2(0.0372±±0.0055)和20J/cm2(0.0343±±0.0043)组其蛋白表达减少(p<0.05)；Smad2mRNA在AKl OJ/cm2(0.01105±0.00238)和20J/cm2(0.00519±0.00119)组,磷酸化水平在20J/cm2组中(0.0160±0.0036)表达减少(p<0.05)；Smad7mRNA和蛋白在正常皮肤(0.00028±±0.00006;0.0093±0.0003)和AK(0.00055±0.00012;0.0096±±0.0009)中表达增加；TβRI, Smad3和Smad4表达未见明显变化(p>0.05)。
结论：1.紫外线照射可能通过抑制AK中TGFβ1/Smad信号通路,促进AK向SCC进展。2.紫外线抑制TGFβ1/Smad信号通路可能与诱导Smad7表达有关。
Part I:Analysis of clinical and pathological features of actinic keratosis
Objective:The incidence of actinic keratosis (AK) increases year by year, and AK could transform into squamous cell carcinoma (SCC) further, which is serious harmful to people's lives and health. In order to improve clinical diagnosis, prevention and treatment level and to minimize morbidity and mortality, the clinical and pathological features of AK was investigated to complete epidemiological data of AK in plateau region.
Methods:Total histopathological confirmed52AKs, which with complete clinical data, were studied retrospectively from department of dermatology of First Affiliated Hospital of Kunming Medical University during2011to2012, and the pathological features were also observed and analyzed carefully. The data were collected and analyzed using SPSS17.0software.
Results:There were52cases of AK diagnosed pathologically between2011and2012. Confirmed AK accounted to0.49%and0.85%of annual pathological examination number, and for annual outpatient ratio was0.18%o and0.34%o respectively. The annal outpatient ratio of2012was increased significantly comparing with2011(x2=5.02, p=0.03);52cases of AK included18males and34females, male:female was1:1.89; The age of onset was45to82years, among them<50years was4cases (7.7%),50to59years was11cases (21.2%),60to69years was17cases (32.7%),70to79years was17cases (32.7%),≥80years was3cases (5.8%), the average age of onset was64.98±9.78,the difference of average age of onset beteween males (62.44±10.76) and femals (66.32±9.11) was not significant (t=-1.372, p=0.176); The main occupation of patients was outdoor workers, such as farmers and construction workers, reached to34cases (65.3%), the diseased parts, age of onset and duration among different occupations were not significantly different (p>0.05); There were27cases (42.3%) of Type III skin according to sun-reactive skin typing, and25cases (57.7%) of Type IV skin, the age of onset and duration between different skin types were not significant different (p>0.05); The main cilinical feature of AK lesions was red-brown, dark-brown pimples with scarly, which accounting to46cases (88.5%), there was one case merged with ulcer and erosion, only the black papules was5cases (9.6%), and cutaneous horn-like was one case (1.9%), all lesions located in the sun-exposed areas of skin, there were25cased in cheek (48.1%),23cases in temporal (44.2%),13cases in nose (25%),11cases in frontal (21.2%), and one in ear (1.9%), one in neck (1.9%), one in hand (1.9%); AK lesions were mainly single (71.2%) in one patient, there were6patients had multi-lesions and the maximum reached21lesions in one patient; The mean lesion diameter was17.87±9.92mm, diameter of lesions was not sifnificantly different between different anatomical site (p>0.05); The mean disease course was44.04±53.09months, male mean disease duration was50.39±29.82months, and female was40.68±62.16months, the average duration of disease between men and women had no significant difference (p>0.05); The dominant pathological type was hypertrophic (51.9%), followed was atrophy (21.2%) and pigmented (15.4%), while acantholytic type (7.7%) and Bowenoid type (3.8%) are relatively rare, and there were2patients combined with SCC; the clinical and pathological diagnosis compliance rate was51.9%among52patients, which was misdiagnosed as seborrheic keratosis13cases, basal cell carcinoma2cases, nevi4cases, common warts3cases, cutaneous horn2cases, and1case of keratoacanthoma.
Conclusion:1. The proportion of diagnosed AK in annual outpatient visits represented an upward trend, which should arouse the whole society's attention;2. AK more often occured in sun-exposed areas of women over the age of50, and main occupation of AK patients was outdoor workers, which demonstrated that close relationship of AK and ultraviolet radiation;3. The clinical features of AK was dominantly represented as red-brown, dark-brown pimples with scarly, mean disease duration was3.6years, and the lesion was single with the average diameter over than1cm;4. The main pathological type was hypertrophic, the low clinical and pathological diagnosis compliance rate needs for the extending of pathological examination, to avoid delaying the disease, which leading to serious consequences;5. The transformation rate of AK to SCC was high, which should be early diagnosis and treatment.
Part II:Mechanistic study of TGFβ1/Smads signaling pathway in actinic keratosis
Objective:The high incidence of actinic keratosis (AK), the precursor of squamous cell carcinoma (SCC), is induced by prolonged exposure to ultraviolet (UV) radiation. UV radiation could also promote transformation of AK to SCC, which is serious harmful to people's lives and health. Transforming growth factor beta1(TGF(31)/Smad signaling pathway acts as a tumor suppressor in early stages, but promotes tumor invasion in later stages. However, the mechanisms of this pathway in AK have not been studied before. In this study, the mechanisms of TGFβ1/Smads signaling pathway in AK was investigated to clarify the pathogenesis of AK.
Methods:AK explants and primary cells were cultured and divided into3groups, Group I is control group, Group II is TGFβ1addition group, and Group III is SB431542addition group. After48h treatment, the tissues and cells were collected respectively for:A. the proliferation and apoptosis analysis with flow cytometry, Ki-67and TUNEL staining; B. the detection of TβRII and Smad2expression changes with real-time PCR and Western blot in AK explants to explore the feasibility of cultured tissue for pathway interference; C. The detection of expression changes of p53, Fas and FasL in AK explants with real-time PCR and Western blot.
Results:A. After12d culture, the keratinocytes of AK showed a typical cobblestone change. The cultured tissues grew well, no significant apoptosis and death was observed. B. After TGFβ1administration, the number of keratinocytes (99.80±6.06), and the percentage of Ki-67was decreased (0.42±0.04) in addition group, the percentage of Ki-67was also decreased in AK tissues (3.90±0.24)(p<0.05). C. Comparing to control, mRNA of Smad2(0.01791±0.00080), the phosphorylated level of TpRI (0.1858±0.0107) and Smad2(0.6112±0.0391) was increased after TGFβ1addition, and the phosphorylated TβRI (0.0644±0.0053) was decreased after SB431542treatment (p<0.05). D. Compared with control, the mRNA (0.00178±0.00010) and protein (0.1620±0.0155) of p53, and the protein (0.4004±0.0267) of Fas was increased (p<0.05).
Conclusion:1. ex vivo culture of skin tissue can be used as the signaling pathway interference model.2. TGFβ1/Smad signaling pathway plays an inhibition role in AK.3. TGFβ1/Smad signaling pathway exerts inhibition effect in AK through induction of p53and Fas.
Part III:The effects of UV radiation on TGFβ1/Smad signalling pathway in AK Objective:UV radiation could promote transformation of AK to SCC, which is serious harmful to people's lives and health. TGFβ1/Smad pathway acts as a tumor suppressor in AK. However, the influence of UV on TGFβ1/Smad signaling pathway have not been studied before. In this study, the effects of UV radiation on TGFβ1/Smad in AK were investigated to clarify the machnisms of progression of AK to SCC.
Methods:The human normal skin and AK tissues were cultured and divided into four groups:OJ/cm2group(control group),5J/cm2group,10J/cm2group, and20J/cm2group. The tissues were respectively radiated on four consecutive days.24hours after radiation, tissues were collected for real time PCR and immunohistochemistry detection of TGFβ1, TβRI, TβRII, Smad2, Smad3, Smad4and Smad7.
Results:A. Comparing to control, the percentage of positive Ki-67cells decreased in the20J/cm2group of normal skin (3.74±1.16)(p<0.05), but was not significantly changed in AK. Compared with control, the TUNEL-positive cells in20J/cm2group of normal skin (39.34±8.73) had increased (P<0.05), and so did the20J/cm2group of AK (25.76±5.99)(P<0.05).B.After radiation,comparing to control,the mRNA and protein level of TGFβ1in the10(0.00821±0.00181;0.1041±0.0064) and20J/cm2(0.01040±0.00145;0.1257±0.0135) groups of normal skin and in the20J/cm2group (0.00504±0.00122;0.0871±0.0038) of AK was up-regulated. However, TβRII, the membrane receptor of TGFβ1, was down-regulated in the20J/cm2groups of both normal skin (0.00119±0.00019;0.0366±0.0052) and AK (0.00073±0.00029;0.0343±0.0043). The mRNA (0.00519±0.00119) and phosphorylated level of Smad2(0.0160±0.0036) was only reduced in the20J/cm2group of AK. In contrast, the inhibitor of TGFβ1/Smad pathway, Smad7, was increased in the20J/cm2groups of both AK (0.00055±0.00012;0.0096±0.0009) and normal skin (0.00028±0.00006;0.0093±0.0003)(P<0.05). The expression of TβRI, Smad3and Smad4had no significant changes (P>0.05).
Conclusion:1. The suppression of TGFβ1/Smad pathway by UV radiation may contribute to the progression of AK to SCC.2.The suppression of UV radiation on TGFβ1/Smad signaling pathway may be associated with the induction of Smad7.
目的：日光性角化病(AK)发病率逐年上升,并可进一步转化为鳞状细胞癌(SCC)。为提高临床诊断、防治水平及最大限度降低患病率及死亡率,完善高原地区AK流行病学资料,本研究就其临床、病理诊断方面的特点进行综合性分析。
方法：采用回顾性研究方法对昆明医科大学第一附属医院皮肤科2011年1月～2012年12月共2年间组织病理确诊、临床资料完整的52例AK患者资料进行分析。对HE组织切片进行观察,分析其病理特征,结果用SPSS17.0统计分析。
结果：2011至2012年间确诊AK52例,确诊AK占当年年病检量比率分别为0.49%和0.85%,占当年年门诊量比率分别为0.18‰和0.34‰,2012年占年门诊量比率比2011年上升(χ2=5.02,p=0.03)；其中男性18人,女性34人,男性：女性为1：1.89；发病年龄为45～82岁,其中<50岁4例(7.7%),50～59岁11例(21.2%),60～69岁17例(32.7%),70～79岁17例(32.7%),>80岁3例(5.8%),平均发病年龄为64.98±9.78,男性平均年龄(62.44±10.76)与女性(66.32±9.11)间无明显差异(t=-1.372,p=0.176)；患者以农民、建筑工人等室外工作者为主,共34例(65.3%),不同职业间的发病部位、发病年龄及病程无明显差别(p>0.05)；日光反应性皮肤分型Ⅲ型皮肤有27例(57.7%),Ⅳ型皮肤有25例(42.3%),不同皮肤类型间发病年龄及病程无明显差别(p>0.05)；AK皮损以红褐色、黑褐色斑丘疹伴鳞屑为主,共46例(88.5%),其中合并糜烂溃疡1例,仅黑色丘疹5例(9.6%),皮角样1例(1.9%),皮损全部分布于曝光部位,以面颊部(25例,48.1%)及颞部(23例,44.2%)多见,其次为鼻部(13例,25%)和额部(11例,21.2%),位于耳、颈及手背各1例(1.9%)；AK皮损以单发为主(71.2%),多于3处皮损患者有6例(11.5%),最多达到21处；皮损平均直径为17.87±9.92mm,不同发病部位皮损直径无明显差别(p>0.05)；病程平均为44.04±53.09月,其中男性平均病程为50.39±29.82,女性为40.68±62.16,男女发病平均病程比较无明显差异(p>0.05)；病理分型以肥厚型为主(51.9%),其次为萎缩型(21.2%)和色素型(15.4%),而棘层松解型(7.7%)和鲍温样型(3.8%)比较少见,其中2例合并SCC；52例病理确诊AK中,临床与病理诊断符合率仅为51.9%,其中误诊为脂溢性角化病13例,基底细胞癌2例,色素痣4例,寻常疣3例,皮角2例,角化棘皮瘤1例。
结论：1、确诊AK占年门诊量比率呈现上升趋势,应引起全社会的重视；2、AK多发于50岁以上女性的头面部曝光部位,以农民等户外工作者为主,与紫外线关系密切；3、AK临床表现多为红褐色、黑褐色斑丘疹伴鳞屑,平均病程为3.6年,以单发皮损为主,平均直径一般大于1cm;4、 AK病理分型以肥厚型为主,临床与病理诊断符合率不高,临床上容易误诊,应增加病检的适用范围,以免贻误病情,造成严重后果；5、AK向SCC转化概率高,应该早期诊断治疗。
第二部分日光性角化病中TGFβ1/Smad信号通路作用机制的研究
目的：AK发病率高,易向SCC转变,但发生发展机制不清。TGFβ1/Smad信号通路在皮肤癌早期抑制肿瘤生长,晚期却促进肿瘤侵袭转移,在AK中的作用机制未见报道。本研究探讨AK中TGFβ1/Smad信号通路的作用机制,阐明AK发生发展的机制。
方法：分别培养人AK组织块及原代细胞,分为三组,第一组对照组,第二组TGFβ1添加培养组,第三组SB431542添加培养组。活性调控处理48h后：①流式细胞术、Ki-67和Tunel染色检测AK细胞和组织增殖凋亡情况；②Real-timePCR和蛋白免疫印迹检测AK组织中TGFβ1/Smad信号通路TβRII和Smad2mRNA表达及蛋白磷酸化水平,检测培养组织块用于信号通路活性调控研究的可行性；③Real-time PCR和蛋白免疫印迹检测AK组织中p53、Fas和FasL mRNA及蛋白表达。
结果：①AK角质细胞培养12天后形态良好,呈典型的铺路石样改变。AK组织培养5天后,皮肤组织生长良好,未见大量细胞凋亡和死亡情况；②在TGFβ1添加培养后,AK角质形成细胞计数减少(99.80±6.06),Ki-67阳性细胞百分比(0.42±0.04)下降,AK组织中Ki-67阳性细胞百分比(3.90±0.24)减少(p<0.05)；③在AK组织块中,与对照组相比,TGFβ1添加后TβRI磷酸化水平(0.1858±0.0]07)增加；Smad2mRNA (0.01791±0.00080)表达增加,磷酸化水平(0.6112±0.0391)增加(p<0.05)。而SB431542添加后,TβRI磷酸化水平(0.0644±0.0053)减少(p6<0.05)；④在TGFβ1添加培养后,AK组织块中p53mRNA表达(0.00178±0.00010)增加,蛋白表达(0.1620±0.0155)增加,Fas蛋白表达(0.4004±0.0267)增加(p<0.05)。
结论：1.皮肤组织块可以作为信号通路活性调控模型。2. TGFβ1/Smad信号通路在AK中发挥抑制细胞增殖作用。3.TGFβ1/Smad信号通路通过促进p53和Fas表达而发挥抑制作用。
第三部分紫外线对日光性角化病中TGFβ1/Smad信号通路影响的研究
目的：紫外线促进日光性角化病(AK)发生及向鳞状细胞癌(SCC)进展,严重危害人民群众生命健康,TGFβ1/Smad信号通路在AK中发挥抑制作用,研究紫外线对TGFβ1/Smad信号通路的影响,阐明紫外线致癌靶点。
方法：分别培养AK和正常皮肤组织,分为四组,第一组为对照组,紫外线照射强度为0J/cm2,第二组为5J/cm2组,第三组为10J/cm2组,第四组为20J/cm2组。组织连续照射4天,继续培养24小时后取材,①Ki-67和Tunel染色检测AK组织增殖凋亡情况；②Real-time PCR和免疫组化检测AK组织中TGFβ1/Smad信号通路TGFβ1, TβRI, TβRII, Smad2, Smad3, Smad4和Smad7mRNA及蛋白表达。
结果：①紫外线照射后,与对照组比较(OJ/cm2组),Ki-67阳性细胞百分率(3.74±1.16)在正常皮肤20J/cm2组中表达减少,凋亡细胞在正常皮肤(39.34±8.73)和AK(25.76±5.99)20J/cm2组中明显增加(p<0.05)；②紫外线照射后,与对照组比较(OJ/cm2组),TGFβ1mRNA在正常皮肤10J/cm2(0.00821±0.00181)和20J/cm2(0.01040±0.00145)组表达增加,其蛋白在10J/cm2(0.1041±0.0064)和20J/cm2(0.1257±0.0135)组表达增加,在AK20J/cm2组其mRNA (0.00504±0.00122)和蛋白(0.0871±±0.0038)表达增加(P<0.05); TβRII mRNA (0.00119±0.00019)和蛋白(0.0366±0.0052)在正常皮肤20J/cm2组表达减少,在AK20J/cm2组其mRNA (0.00073±0.00029),在10J/cm2(0.0372±±0.0055)和20J/cm2(0.0343±±0.0043)组其蛋白表达减少(p<0.05)；Smad2mRNA在AKl OJ/cm2(0.01105±0.00238)和20J/cm2(0.00519±0.00119)组,磷酸化水平在20J/cm2组中(0.0160±0.0036)表达减少(p<0.05)；Smad7mRNA和蛋白在正常皮肤(0.00028±±0.00006;0.0093±0.0003)和AK(0.00055±0.00012;0.0096±±0.0009)中表达增加；TβRI, Smad3和Smad4表达未见明显变化(p>0.05)。
结论：1.紫外线照射可能通过抑制AK中TGFβ1/Smad信号通路,促进AK向SCC进展。2.紫外线抑制TGFβ1/Smad信号通路可能与诱导Smad7表达有关。
Part I:Analysis of clinical and pathological features of actinic keratosis
Objective:The incidence of actinic keratosis (AK) increases year by year, and AK could transform into squamous cell carcinoma (SCC) further, which is serious harmful to people's lives and health. In order to improve clinical diagnosis, prevention and treatment level and to minimize morbidity and mortality, the clinical and pathological features of AK was investigated to complete epidemiological data of AK in plateau region.
Methods:Total histopathological confirmed52AKs, which with complete clinical data, were studied retrospectively from department of dermatology of First Affiliated Hospital of Kunming Medical University during2011to2012, and the pathological features were also observed and analyzed carefully. The data were collected and analyzed using SPSS17.0software.
Results:There were52cases of AK diagnosed pathologically between2011and2012. Confirmed AK accounted to0.49%and0.85%of annual pathological examination number, and for annual outpatient ratio was0.18%o and0.34%o respectively. The annal outpatient ratio of2012was increased significantly comparing with2011(x2=5.02, p=0.03);52cases of AK included18males and34females, male:female was1:1.89; The age of onset was45to82years, among them<50years was4cases (7.7%),50to59years was11cases (21.2%),60to69years was17cases (32.7%),70to79years was17cases (32.7%),≥80years was3cases (5.8%), the average age of onset was64.98±9.78,the difference of average age of onset beteween males (62.44±10.76) and femals (66.32±9.11) was not significant (t=-1.372, p=0.176); The main occupation of patients was outdoor workers, such as farmers and construction workers, reached to34cases (65.3%), the diseased parts, age of onset and duration among different occupations were not significantly different (p>0.05); There were27cases (42.3%) of Type III skin according to sun-reactive skin typing, and25cases (57.7%) of Type IV skin, the age of onset and duration between different skin types were not significant different (p>0.05); The main cilinical feature of AK lesions was red-brown, dark-brown pimples with scarly, which accounting to46cases (88.5%), there was one case merged with ulcer and erosion, only the black papules was5cases (9.6%), and cutaneous horn-like was one case (1.9%), all lesions located in the sun-exposed areas of skin, there were25cased in cheek (48.1%),23cases in temporal (44.2%),13cases in nose (25%),11cases in frontal (21.2%), and one in ear (1.9%), one in neck (1.9%), one in hand (1.9%); AK lesions were mainly single (71.2%) in one patient, there were6patients had multi-lesions and the maximum reached21lesions in one patient; The mean lesion diameter was17.87±9.92mm, diameter of lesions was not sifnificantly different between different anatomical site (p>0.05); The mean disease course was44.04±53.09months, male mean disease duration was50.39±29.82months, and female was40.68±62.16months, the average duration of disease between men and women had no significant difference (p>0.05); The dominant pathological type was hypertrophic (51.9%), followed was atrophy (21.2%) and pigmented (15.4%), while acantholytic type (7.7%) and Bowenoid type (3.8%) are relatively rare, and there were2patients combined with SCC; the clinical and pathological diagnosis compliance rate was51.9%among52patients, which was misdiagnosed as seborrheic keratosis13cases, basal cell carcinoma2cases, nevi4cases, common warts3cases, cutaneous horn2cases, and1case of keratoacanthoma.
Conclusion:1. The proportion of diagnosed AK in annual outpatient visits represented an upward trend, which should arouse the whole society's attention;2. AK more often occured in sun-exposed areas of women over the age of50, and main occupation of AK patients was outdoor workers, which demonstrated that close relationship of AK and ultraviolet radiation;3. The clinical features of AK was dominantly represented as red-brown, dark-brown pimples with scarly, mean disease duration was3.6years, and the lesion was single with the average diameter over than1cm;4. The main pathological type was hypertrophic, the low clinical and pathological diagnosis compliance rate needs for the extending of pathological examination, to avoid delaying the disease, which leading to serious consequences;5. The transformation rate of AK to SCC was high, which should be early diagnosis and treatment.
Part II:Mechanistic study of TGFβ1/Smads signaling pathway in actinic keratosis
Objective:The high incidence of actinic keratosis (AK), the precursor of squamous cell carcinoma (SCC), is induced by prolonged exposure to ultraviolet (UV) radiation. UV radiation could also promote transformation of AK to SCC, which is serious harmful to people's lives and health. Transforming growth factor beta1(TGF(31)/Smad signaling pathway acts as a tumor suppressor in early stages, but promotes tumor invasion in later stages. However, the mechanisms of this pathway in AK have not been studied before. In this study, the mechanisms of TGFβ1/Smads signaling pathway in AK was investigated to clarify the pathogenesis of AK.
Methods:AK explants and primary cells were cultured and divided into3groups, Group I is control group, Group II is TGFβ1addition group, and Group III is SB431542addition group. After48h treatment, the tissues and cells were collected respectively for:A. the proliferation and apoptosis analysis with flow cytometry, Ki-67and TUNEL staining; B. the detection of TβRII and Smad2expression changes with real-time PCR and Western blot in AK explants to explore the feasibility of cultured tissue for pathway interference; C. The detection of expression changes of p53, Fas and FasL in AK explants with real-time PCR and Western blot.
Results:A. After12d culture, the keratinocytes of AK showed a typical cobblestone change. The cultured tissues grew well, no significant apoptosis and death was observed. B. After TGFβ1administration, the number of keratinocytes (99.80±6.06), and the percentage of Ki-67was decreased (0.42±0.04) in addition group, the percentage of Ki-67was also decreased in AK tissues (3.90±0.24)(p<0.05). C. Comparing to control, mRNA of Smad2(0.01791±0.00080), the phosphorylated level of TpRI (0.1858±0.0107) and Smad2(0.6112±0.0391) was increased after TGFβ1addition, and the phosphorylated TβRI (0.0644±0.0053) was decreased after SB431542treatment (p<0.05). D. Compared with control, the mRNA (0.00178±0.00010) and protein (0.1620±0.0155) of p53, and the protein (0.4004±0.0267) of Fas was increased (p<0.05).
Conclusion:1. ex vivo culture of skin tissue can be used as the signaling pathway interference model.2. TGFβ1/Smad signaling pathway plays an inhibition role in AK.3. TGFβ1/Smad signaling pathway exerts inhibition effect in AK through induction of p53and Fas.
Part III:The effects of UV radiation on TGFβ1/Smad signalling pathway in AK Objective:UV radiation could promote transformation of AK to SCC, which is serious harmful to people's lives and health. TGFβ1/Smad pathway acts as a tumor suppressor in AK. However, the influence of UV on TGFβ1/Smad signaling pathway have not been studied before. In this study, the effects of UV radiation on TGFβ1/Smad in AK were investigated to clarify the machnisms of progression of AK to SCC.
Methods:The human normal skin and AK tissues were cultured and divided into four groups:OJ/cm2group(control group),5J/cm2group,10J/cm2group, and20J/cm2group. The tissues were respectively radiated on four consecutive days.24hours after radiation, tissues were collected for real time PCR and immunohistochemistry detection of TGFβ1, TβRI, TβRII, Smad2, Smad3, Smad4and Smad7.
Results:A. Comparing to control, the percentage of positive Ki-67cells decreased in the20J/cm2group of normal skin (3.74±1.16)(p<0.05), but was not significantly changed in AK. Compared with control, the TUNEL-positive cells in20J/cm2group of normal skin (39.34±8.73) had increased (P<0.05), and so did the20J/cm2group of AK (25.76±5.99)(P<0.05).B.After radiation,comparing to control,the mRNA and protein level of TGFβ1in the10(0.00821±0.00181;0.1041±0.0064) and20J/cm2(0.01040±0.00145;0.1257±0.0135) groups of normal skin and in the20J/cm2group (0.00504±0.00122;0.0871±0.0038) of AK was up-regulated. However, TβRII, the membrane receptor of TGFβ1, was down-regulated in the20J/cm2groups of both normal skin (0.00119±0.00019;0.0366±0.0052) and AK (0.00073±0.00029;0.0343±0.0043). The mRNA (0.00519±0.00119) and phosphorylated level of Smad2(0.0160±0.0036) was only reduced in the20J/cm2group of AK. In contrast, the inhibitor of TGFβ1/Smad pathway, Smad7, was increased in the20J/cm2groups of both AK (0.00055±0.00012;0.0096±0.0009) and normal skin (0.00028±0.00006;0.0093±0.0003)(P<0.05). The expression of TβRI, Smad3and Smad4had no significant changes (P>0.05).
Conclusion:1. The suppression of TGFβ1/Smad pathway by UV radiation may contribute to the progression of AK to SCC.2.The suppression of UV radiation on TGFβ1/Smad signaling pathway may be associated with the induction of Smad7.
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